Oxazole compound and pharmaceutical composition

ABSTRACT

The present invention provides a oxazole compound represented by Formula (1), or a salt thereof: 
                         
wherein R 1  is an aryl group which may have one or more substituents; R 2  is an aryl group or a nitrogen atom-containing heterocyclic group each of which may have one or more substituents; and W is a divalent group represented by —Y 1 -A 1 - or or —Y 2 —C(═O)— wherein Y 1  is a group such as —C(═O)—, A 1  is a group such as a lower alkylene group, and Y 2  is a group such as a piperazinediyl group. The oxazole compound has a specific inhibitory action against phosphodiesterase 4.

This patent application is a reissue application of U.S. Pat. No.8,637,559, issued Jan. 28, 2014, on application Ser. No. 12/090,951, §371(c) date of Mar. 26, 2009, which is the National Stage ofPCT/JP2006/323066, filed Nov. 14, 2006.

TECHNICAL FIELD

The present invention relates to new oxazole compounds andpharmaceutical compositions.

BACKGROUND ART

Various oxazole compounds have been developed and are disclosed indocuments such as WO 03/072102, WO 98/15274, etc. However, the oxazolecompounds of the present invention are not disclosed in any literature.

Some compounds having a specific inhibitory action againstphosphodiesterase 4 (PDE4) have been reported. However, known PDE4inhibitors have problems of side effects such as vomit induction,nausea, etc. and/or a defect of insufficient PDE4 inhibitory action.Therefore, known PDE4 inhibitors are not clinically used as therapeuticagents.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a compound that has aPDE4 inhibitory action and is free from the above-mentioned problems ofthe prior art.

The present inventors conducted extensive research to solve the aboveproblems, and succeeded in synthesizing an oxazole compound with a novelstructure, the compound having high specificity and a strong PDE4inhibitory action. Further, the present inventors found that the oxazolecompound is capable of exhibiting preventive and/or therapeutic effectson PDE-mediated diseases, and in particular atopic dermatitis, based onits PDE4 inhibitory action. Furthermore, the inventors found that thecompound has low penetration into blood when administered transdermally,and thus has low systemic side effects.

The present inventors further found that the oxazole compound is capableof exhibiting a tumor necrosis factor-α (TNF-α) production inhibitoryaction.

In chronic inflammatory diseases such as autoimmune diseases andallergic diseases, cytokines produced by immunocompetent cells are knownto be important inflammatory mediators, and among such cytokines, TNF-αis presumed to play a particularly important role. Therefore, theoxazole compound of the present invention is extremely effective for thetreatment of TNF-α-mediated diseases.

The present invention has been accomplished by further research based onthe above findings.

The present invention provides a oxazole compound, a pharmaceuticalcomposition comprising said compound, a use of said compound, a methodfor treating or preventing a disorder, and a process for producing saidcompound, as described in Item 1 to 14 below.

Item 1. An oxazole compound represented by Formula (1)

wherein R¹ is an aryl group which may have one or more substituentsselected from the following (1-1) to (1-11):(1-1) hydroxy groups,(1-2) unsubstituted or halogen-substituted lower alkoxy groups,(1-3) lower alkenyloxy groups,(1-4) lower alkynyloxy groups,(1-5) cyclo C₃₋₈ alkyl lower alkoxy groups,(1-6) cyclo C₃₋₈ alkyloxy groups,(1-7) cyclo C₃₋₈ alkenyloxy groups,(1-8) dihydroindenyloxy groups,(1-9) hydroxy lower alkoxy groups,(1-10) oxiranyl lower alkoxy groups, and(1-11) protected hydroxy groups;R² is an aryl group or a nitrogen atom-containing heterocyclic groupeach of which may have one or more substituents selected from thefollowing (2-1) to (2-10):(2-1) hydroxy groups,(2-2) unsubstituted or halogen-substituted lower alkoxy groups,(2-3) unsubstituted or halogen-substituted lower alkyl groups,(2-4) lower alkenyloxy groups,(2-5) halogen atoms,(2-6) lower alkanoyl groups,(2-7) lower alkylthio groups,(2-8) lower alkylsulfonyl groups,(2-9) oxo groups, and(2-10) lower alkoxy lower alkoxy groups; andW is a divalent group represented by Formula (i) or (ii):Formula (i) —Y¹-A¹-Formula (ii) —Y²—C(═O)—wherein A¹ is a lower alkenylene group, or a lower alkylene group whichmay have one or more substituents selected from the group consisting ofhydroxy groups and lower alkoxycarbonyl groups, Y¹ is a direct bond,—C(═O)—, —C(═O)—N(R³)—, —N(R⁴)—C(═O)—, —S(O)_(m)—NH—, or —S(O)_(n)—wherein R³ and R⁴ are each independently a hydrogen atom or a loweralkyl group, andm and n are each independently an integer from 0 to 2, andY² is a piperazinediyl group, or a divalent group represented by Formula(iii) or (iv):Formula (iii) —C(═O)-A²-N(R⁵)—Formula (iv) -A³-N(R⁶)—wherein A² and A³ are each independently a lower alkylene group, and R⁵and R⁶ are each independently a hydrogen atom or a lower alkyl group;or a salt thereof.

Item 2. The compound according to item 1, wherein R¹ is a phenyl groupwhich has 1 to 3 substituents selected from the following (1-2), (1-3),(1-4) and (1-5):

(1-2) unsubstituted or halogen-substituted lower alkoxy groups,

(1-3) lower alkenyloxy groups,

(1-4) lower alkynyloxy groups, and

(1-5) cyclo C₃₋₈ alkyl lower alkoxy groups;

R² is a phenyl group or a pyridyl group each of which may have 1 to 3substituents selected from the group consisting of the following (2-2),(2-3), (2-4) and (2-5):

(2-2) unsubstituted or halogen-substituted lower alkoxy groups,

(2-3) unsubstituted or halogen-substituted lower alkyl groups,

(2-4) lower alkenyloxy groups, and

(2-5) halogen atoms;

W is a divalent group represented by Formula (i):—Y¹-A¹-   Formula (i)wherein A¹ is a lower alkylene group, andY¹ is —C(═O)— or —C(═O)—N(R³)—wherein R³ is a hydrogen atom.

Item 3. The compound according to item 2, wherein R¹ is a phenyl grouphaving two substituents selected from the following (1-2), (1-3), (1-4)and (1-5):

(1-2) unsubstituted or halogen-substituted lower alkoxy groups,

(1-3) lower alkenyloxy groups,

(1-4) lower alkynyloxy groups, and

(1-5) cyclo C₃₋₈ alkyl lower alkoxy groups;

R² is a phenyl group or a pyridyl group each of which may have 1 to 2substituents selected from the following (2-2), (2-3), (2-4) and (2-5):

(2-2) unsubstituted or halogen-substituted lower alkoxy groups,

(2-3) unsubstituted or halogen-substituted lower alkyl groups,

(2-4) lower alkenyloxy groups, and

(2-5) halogen atoms; and

W is a divalent group represented by Formula (i):—Y¹-A¹-   Formula (i)wherein A¹ is a lower alkylene group, andY¹ is —C(═O)— or —C(═O)—N(R³)—wherein R³ is a hydrogen atom.

Item 4. The compound according to item 3, wherein R¹ is a phenyl groupsubstituted on the phenyl ring with two lower alkoxy groups, a phenylgroup substituted on the phenyl ring with one lower alkoxy group and oneCyclo C₃₋₈ alkyl lower alkoxy group, a phenyl group substituted on thephenyl ring with one lower alkoxy group and one halogen-substitutedlower alkoxy group, a phenyl group substituted on the phenyl group withone lower alkoxy group and one lower alkenyloxy group, a phenyl groupsubstituted on the phenyl ring with one halogen-substituted lower alkoxygroup and one cyclo C₃₋₈ alkyl lower alkoxy group, a phenyl groupsubstituted on the phenyl ring with one halogen-substituted lower alkoxygroup and one lower alkenyloxy group, or a phenyl group substituted onthe phenyl ring with two halogen-substituted lower alkoxy groups;

R² is a lower alkoxyphenyl group, a lower alkenyloxyphenyl group, ahalogen-substituted lower alkoxyphenyl group, a lower alkylpyridylgroup, or a phenyl group substituted on the phenyl ring with one loweralkoxy group and one halogen atom; and

W is a divalent group represented by Formula (i):—Y¹-A¹-   Formula (i)wherein A¹ is a C₁₋₄ alkylene group, andY¹ is —C(═O)— or —C(═O)—N(R³)—wherein R³ is a hydrogen atom.

Item 5. The compound according to item 4, wherein R¹ is a phenyl groupsubstituted on the phenyl ring with two lower alkoxy groups, a phenylgroup substituted on the phenyl ring with one lower alkoxy group and onecyclo C₃₋₈ alkyl lower alkoxy group, a phenyl group substituted on thephenyl ring with one lower alkoxy group and one halogen-substitutedlower alkoxy group, a phenyl group substituted on the phenyl group withone lower alkoxy group and one lower alkenyloxy group, a phenyl groupsubstituted on the phenyl ring with one halogen-substituted lower alkoxygroup and one cyclo C₃₋₈ alkyl lower alkoxy group, a phenyl groupsubstituted on the phenyl ring with one halogen-substituted lower alkoxygroup and one lower alkenyloxy group, or a phenyl group substituted onthe phenyl ring with two halogen-substituted lower alkoxy groups;

R² is a lower alkoxyphenyl group, a lower alkenyloxy phenyl group, ahalogen-substituted lower alkoxyphenyl group, a lower alkylpyridylgroup, or a phenyl group substituted on the phenyl ring with one loweralkoxy group and one halogen atom; and

W is a divalent group represented by Formula (i)—Y¹-A¹-   Formula (i)wherein A¹ is a C₁₋₄ alkylene group, andY¹ is —C(═O)—.

Item 6. The compound according to item 4, wherein R¹ is a phenyl groupsubstituted on the phenyl ring with one lower alkoxy group and onehalogen-substituted lower alkoxy group, a phenyl group substituted onthe phenyl ring with one halogen-substituted lower alkoxy group and onecyclo C₃₋₈ alkyl lower alkoxy group, or a phenyl group substituted onthe phenyl ring with one halogen-substituted lower alkoxy group and onelower alkenyloxy group;

R² is a lower alkoxyphenyl group or a lower alkylpyridyl group; and

W is a divalent group represented by Formula (i):—Y¹-A¹-   Formula (i)wherein A¹ is a C₁₋₄ alkylene group, andY¹ is —C(═O)—N(R³)—wherein R³ is a hydrogen atom.

Item 7. A pharmaceutical composition comprising the compound or saltaccording to any one of items 1 to 6 as an active ingredient and apharmaceutically acceptable carrier.

Item 8. A pharmaceutical composition for treating or preventingphosphodiesterase 4-mediated and/or tumor necrosis factor-α-mediateddiseases, the composition comprising the compound or salt according toany one of items 1 to 6.

Item 9. A pharmaceutical composition for treating or preventing atopicdermatitis, the composition comprising the compound or salt according toany one of items 1 to 6.

Item 10. A process for producing a pharmaceutical composition, theprocess comprising mixing the compound or salt according to any one ofitems 1 to 6 with a pharmaceutically acceptable carrier.

Item 11. Use of the compound or salt according to any one of items 1 to6 as a drug.

Item 12. Use of the compound or salt according to any one of items 1 to6 as a phosphodiesterase 4 inhibitor and/or tumor necrosis factor-αproduction inhibitor.

Item 13. A method for treating or preventing phosphodiesterase4-mediated and/or tumor necrosis factor-α-mediated diseases, the methodcomprising administering the compound or salt according to any one ofitems 1 to 6 to human or animal.

Item 14. A process for producing an oxazole compound represented byFormula (1):

wherein R¹, R² and W are the same as defined in item 1, or a saltthereof, the process comprising a reaction of a compound represented byFormula (2):

wherein R² and W are the same as defined above, and X is a halogen atom,or a salt thereof, with a compound represented by Formula (3):

wherein R¹ is the same as defined above, or a salt thereof.

In Formula (1), R¹ is preferably a phenyl group. The phenyl grouprepresented by R¹ preferably has 1 to 3, and more preferably 2,substituents selected from the group consisting of (1-2) unsubstitutedor halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxygroups, (1-4) lower alkynyloxy groups, and (1-5) cyclo C₃₋₈ alkyl loweralkoxy groups.

In Formula (1), R² is preferably a phenyl group or a pyridyl group. Thephenyl group or pyridyl group represented by R² preferably has 1 to 3,and more preferably 1, substituents selected from the group consistingof (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3)unsubstituted or halogen-substituted lower alkyl groups, (2-4) loweralkenyloxy groups, and (2-5) halogen atoms.

In Formula (1), W is preferably a divalent group represented by Formula(i) —Y¹-A¹-. A is preferably a lower alkylene group; Y¹ is preferably—C(═O)— or —C(═O)—N(R³)—; and R³ is preferably a hydrogen atom.

Among the oxazole compounds of the present invention, those representedby Formula (1A) and salts thereof are preferable, and those representedby Formula (1B) and salts thereof are more preferable.

Formula (1A):

wherein R¹ is a phenyl group having two substituents selected from thefollowing (1-2), (1-3), (1-4) and (1-5):(1-2) unsubstituted or halogen-substituted lower alkoxy groups,(1-3) lower alkenyloxy groups,(1-4) lower alkynyloxy groups, and(1-5) cyclo C₃₋₈ alkyl lower alkoxy groups;R² is a phenyl group or a pyridyl group each of which may have one ormore substituents selected from the following (2-2), (2-3), (2-4) and(2-5):(2-2) unsubstituted or halogen-substituted lower alkoxy groups,(2-3) unsubstituted or halogen-substituted lower alkyl groups,(2-4) lower alkenyloxy groups, and(2-5) halogen atoms; andW is a divalent group represented by Formula (i):—Y¹-A¹-   Formula (i)wherein A¹ is a lower alkylene group, andY¹ is —C(═O)— or —C(═O)—N(R³)—wherein R³ is a hydrogen atom.

Formula (1B):

wherein R¹ is a phenyl group substituted on the phenyl ring with twolower alkoxy groups, a phenyl group substituted on the phenyl ring withone lower alkoxy group and one cyclo C₃₋₈ alkyl lower alkoxy group, aphenyl group substituted on the phenyl ring with one lower alkoxy groupand one halogen-substituted lower alkoxy group, a phenyl groupsubstituted on the phenyl group with one lower alkoxy group and onelower alkenyloxy group, a phenyl group substituted on the phenyl ringwith one halogen-substituted lower alkoxy group and one cyclo C₃₋₈ alkyllower alkoxy group, a phenyl group substituted on the phenyl ring withone halogen-substituted lower alkoxy group and one lower alkenyloxygroup, or a phenyl group substituted on the phenyl ring with twohalogen-substituted lower alkoxy groups;R² is a lower alkoxyphenyl group, a lower alkenyloxyphenyl group, ahalogen-substituted lower alkoxyphenyl group, a lower alkylpyridylgroup, or a phenyl group substituted on the phenyl ring with one loweralkoxy group and one halogen atom; andW is a divalent group represented by Formula (i):—Y¹-A¹-   Formula (i)wherein A¹ is a C₁₋₄ alkylene group, andY¹ is —C(═O)— or —C(═O)—N(R³)—wherein R³ is a hydrogen atom.

The present invention is described below in further detail.

Compound Represented by Formula (1)

In Formula (1), R¹ is an aryl group. The aryl group may have 1 to 3, andpreferably 2, substituents selected from the group consisting of (1-1)hydroxy groups, (1-2) unsubstituted or halogen-substituted lower alkoxygroups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups,(1-5) cyclo C₃₋₈ alkyl lower alkoxy groups, (1-6) cyclo C₃₋₈ alkyloxygroups, (1-7) cyclo C₃₋₈ alkenyloxy groups, (1-8) dihydroindenyloxygroups, (1-9) hydroxy lower alkoxy groups, (1-10) oxiranyl lower alkoxygroups, and (1-11) protected hydroxy groups.

In Formula (1), R² is an aryl group or a nitrogen atom-containingheterocyclic group. The aryl group and heterocyclic group may have 1 to3, and preferably 1, substituent selected from the group consisting of(2-1) hydroxy groups, (2-2) unsubstituted or halogen-substituted loweralkoxy groups, (2-3) unsubstituted or halogen-substituted lower alkylgroups, (2-4) lower alkenyloxy groups, (2-5) halogen atoms, (2-6) loweralkanoyl groups, (2-7) lower alkylthio groups, (2-8) lower alkylsulfonylgroups, (2-9) oxo groups, and (2-10) lower alkoxy lower alkoxy groups.

In Formula (1), W is a divalent group represented by Formula (i) or(ii):—Y¹-A¹-   Formula (i)—Y²—C(═O)—  Formula (ii)wherein A¹ is a lower alkenylene group, or a lower alkylene group whichmay have 1 to 3, and preferably 1, substituent selected from the groupconsisting of hydroxy groups and lower alkoxycarbonyl groups;Y¹ is a direct bond, —C(═O)—, —C(═O)—N(R³)—, —N(R⁴)—C(═O)—,—S(O)_(m)—NH—, or —S(O)_(n)—wherein R³ and R⁴ are each independently a hydrogen atom or a loweralkyl group, and m and n are each independently an integer from 0 to 2;andY² is a piperazinediyl group, or a divalent group represented by Formula(iii) or (iv):—C(═O)-A²-N(R⁵)—  Formula (iii)-A³-N(R⁶)—  Formula (iv)wherein A² and A³ are each independently a lower alkylene group, andR⁵ and R⁶ are each independently a hydrogen atom or a lower alkyl group.

Examples of aryl groups include phenyl, naphthyl, etc.

Examples of halogen atoms include fluorine, chlorine, bromine, iodine,etc.

Lower alkyl groups are straight- or branched-chain alkyl groups having 1to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-ethylpropyl,n-pentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, etc.

Unsubstituted or halogen-substituted lower alkyl groups are straight- orbranched-chain alkyl groups having 1 to 6 carbon atoms as defined above,or such alkyl groups substituted with 1 to 7 halogen atoms. Examplesthereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, 1-ethylpropyl, n-pentyl, neopentyl, n-hexyl,isohexyl, 3-methyl pentyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,bromomethyl, dibromomethyl, dichlorofluoromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl,heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl,4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl,4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5-chloropentyl,6,6,6-trifluorohexyl, 6-chlorohexyl, etc.

Lower alkenyloxy groups are groups composed of an oxygen atom and a C₂₋₆straight- or branched-chain alkenyl group having 1 to 3 double bonds.Lower alkenyloxy groups have cis and trans forms. More specific examplesthereof include vinyloxy, 1-propenyloxy, 2-propenyloxy,1-methyl-1-propenyloxy, 2-methyl-1-propenyloxy, 2-methyl-2-propenyloxy,2-propenyloxy, 2-butenyloxy, 1-butenyloxy, 3-butenyloxy, 2-pentenyloxy,1-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 1,3-butadienyloxy,1,3-pentadienyloxy, 2-penten-4-yloxy, 3-methyl-2-butenyloxy,2-hexenyloxy, 1-hexenyloxy, 5-hexenyloxy, 3-hexenyloxy, 4-hexenyloxy,3,3-dimethyl-1-propenyloxy, 2-ethyl-1-propenyloxy, 1,3,5-hexatrienyloxy,1,3-hexadienyloxy, 1,4-hexadienyloxy, etc.

Examples of lower alkynyloxy groups include groups composed of an oxygenatom and a C₂₋₆ straight- or branched-chain alkynyl group having 1 to 3triple bonds. More specific examples thereof include ethynyloxy,2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 1-methyl-2-propynyloxy,2-pentynyloxy, 2-hexynyloxy, etc.

Examples of cyclo C₃₋₈ alkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

Preferable examples of lower alkoxy groups include C₁₋₆ straight- orbranched-chain alkoxy groups. Specifically, such groups include methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy,sec-butoxy, 1-ethylpropoxy, n-pentoxy, neopentoxy, n-hexyloxy,isohexyloxy, 3-methylpentoxy, etc.

Examples of cyclo C₃₋₈ alkyl lower alkoxy groups include theabove-mentioned lower alkoxy groups which have 1 to 3, and preferably 1,cyclo C₃₋₈ alkyl group as listed above. More specific examples thereofinclude cyclopropylmethoxy, cyclobutylmethoxy, cyclohexylmethoxy,2-cyclopropylethoxy, 1-cyclobutylethoxy, cyclopentylmethoxy,3-cyclopentylpropoxy, 4-cyclohexylbutoxy, 5-cycloheptylpentoxy,6-cyclooctylhexyloxy, 1,1-dimethyl-2-cyclohexylethoxy,2-methyl-3-cyclopropylpropoxy, etc.

Examples of cyclo C₃₋₈ alkyloxy groups include cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,cyclooctyloxy, etc.

Examples of cyclo C₃₋₈ alkenyloxy groups include cyclopropenyloxy,cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy,cyclooctenyloxy, etc.

Examples of dihydroindenyloxy groups include 2,3-dihydroinden-1-yloxy,2,3-dihydroinden-2-yloxy, etc.

Examples of hydroxy lower alkoxy groups include lower alkoxy groups(preferably C₁₋₆ straight- or branched-chain alkoxy groups) having 1 to5, and preferably 1 to 3, hydroxy groups. More specific examples thereofinclude hydroxymethyloxy, 2-hydroxyethyloxy, 1-hydroxyethyloxy,3-hydroxypropyloxy, 2,3-dihydroxypropyloxy, 4-hydroxybutyloxy,3,4-dihydroxybutyloxy, 1,1-dimethyl-2-hydroxyethyloxy,5-hydroxypentyloxy, 6-hydroxyhexyloxy, 3,3-dimethyl-3-hydroxypropyloxy,2-methyl-3-hydroxypropyloxy, 2,3,4-trihydroxybutyloxy,perhydroxyhexyloxy, etc.

Examples of oxiranyl lower alkoxy groups include C₁₋₆ straight- orbranched-chain alkoxy groups having 1 or 2 oxyranyl groups such as, forexample, oxiranylmethoxy, 2-oxiranylethoxy, 1-oxiranylethoxy,3-oxiranylpropoxy, 4-oxiranylbutoxy, 5-oxiranylpentyloxy,6-oxiranylhexyloxy, 1,1-dimethyl-2-oxiranylethoxy,2-methyl-3-oxiranylpropoxy, etc.

Examples of protecting groups of protected hydroxy groups include loweralkanoyl and other acyl groups; phenyl (lower)alkyl groups which mayhave one or more suitable substituents (e.g., benzyl, phenethyl,3-phenylpropyl, 4-methoxybenzyl, trityl, etc.); trisubstituted silylgroups [e.g., tri(lower)alkylsilyl groups (e.g., trimethylsilyl,t-butyldimethylsilyl, etc.) and the like]; tetrahydropyranyl; etc.

Examples of nitrogen atom-containing heterocyclic groups includepyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl,piperazinyl, octahydroisoindolyl, azepanyl, azocanyl, pyrrolyl,dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl,dihydrotriazolyl, pyrazolyl, pyridyl and N-oxides thereof,dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl,dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl, isoindolyl,indolinyl, isoindolinyl, hexahydroisoindolinyl, benzoimidazolyl,quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl,benzotriazolyl, carbazolyl, oxazolyl, isooxazolyl, oxadiazolyl,oxazolidinyl, isooxazolidinyl, morpholinylbenzoxazolyl,dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl,benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl,thiadiazolyl, dihydrothiazinyl, thiazolyzinyl, benzothiazolyl,benzothiadiazolyl, etc.

Unsubstituted or halogen-substituted lower alkoxy groups are straight-or branched-chain alkoxy groups having 1 to 6 carbon atoms, or suchalkoxy groups substituted with 1 to 7 halogen atoms. Examples thereofinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, sec-butoxy, 1-ethylpropoxy, n-pentoxy, neopentoxy,n-hexyloxy, isohexyloxy, 3-methylpentoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy,2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy, 2-chloroethoxy, 3,3,3-trifluoropropoxy,heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy,2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy,4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy,2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropentoxy,6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, etc.

Examples of lower alkanoyl groups include formyl, acetyl, propionyl,butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, and otherC₁₋₆ straight- or branched-chain alkanoyl groups.

Examples of lower alkylthio groups include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio,n-hexylthio, and other C₁₋₆ straight- or branched-chain alkylthiogroups.

Preferable examples of lower alkylsulfonyl groups include C₁₋₆ straight-or branched-chain alkylsulfonyl groups. More specific examples thereofinclude methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl,tert-butylsulfonyl, sec-butylsulfonyl, n-pentylsulfonyl,isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl,3-methylpentylsulfonyl, etc.

Lower alkenylene groups include, for example, vinylidene, propylene,butenylene, and other C₂₋₆ straight- or branched-chain alkenylene groupshaving 1 to 3 double bonds.

Preferable examples of lower alkoxycarbonyl groups include groupscomposed of a C₁₋₆ straight- or branched-chain alkoxy group and acarbonyl group. Specific examples thereof include methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl,n-pentoxycarbonyl, neopentoxycarbonyl, n-hexyloxycarbonyl,isohexyloxycarbonyl, 3-methylpentoxycarbonyl, etc.

Lower alkylene groups include, for example, ethylene, trimethylene,2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene,methylmethylene, ethylmethylene, tetramethylene, pentamethylene,hexamethylene, and other C₁₋₆ straight- or branched-chain alkylenegroups.

Examples of lower alkoxy lower alkoxy groups include alkoxyalkoxy groupsin which the two alkoxy moieties are each independently a C₁₋₆ straight-or branched-chain alkoxy group. Specific examples thereof includemethoxymethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy,5-methoxypentoxy, 6-methoxyhexyloxy, ethoxymethoxy, 2-ethoxyethoxy,n-propoxymethoxy, isopropoxymethoxy, n-butoxymethoxy, etc.

Examples of C₁₋₄ alkylene groups include ethylene, trimethylene,2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene,methylmethylene, ethylmethylene, tetramethylene, and other C₁₋₄straight- or branched-chain alkylene groups.

Production Process for Compound Represented by Formula (1)

The oxazole compound represented by Formula (1) can be produced byvarious processes, one example of which is shown in Reaction Scheme 1.

wherein R¹, R² and W are as defined in Formula (1), and X is a halogenatom.

Compound (1) is produced by reacting Compound (2) with Compound (3).

The reaction of Compound (2) with Compound (3) is usually performed in asuitable solvent. A wide variety of known solvents can be used as longas they do not inhibit the reaction. Examples of such solvents includedimethylformamide, dimethylsulfoxide, acetonitrile, and other aproticpolar solvents; acetone, methyl ethyl ketone, and other ketone solvents;benzene, toluene, xylene, tetralin, liquid paraffin, and otherhydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol,tert-butanol, and other alcohol solvents; tetrahydrofuran, dioxane,dipropyl ether, diethyl ether, dimethoxyethane, diglyme, and other ethersolvents; ethyl acetate, methyl acetate, and other ester solvents;mixtures thereof; etc. Such solvents may contain water.

The proportion of Compound (3) to Compound (2) is usually 0.5 to 5 mol,and preferably 0.5 to 3 mol, per mol of Compound (2).

The reaction of Compound (2) with Compound (3) is usually performed bycontinuing stirring at −20 to 200° C., and preferably at 0 to 150° C.,for 30 minutes to 60 hours, and preferably 1 to 30 hours.

Compound (3) used as a starting material is an easily available knowncompound. Compound (2) encompasses novel compounds, and a productionprocess for such a compound is described hereinafter (Reaction Scheme9).

Among the oxazole compounds represented by Formula (1), those in which Wis a divalent group represented by —Y¹-A¹- wherein Y¹ is —C(═O)—N(R³)—(hereinafter referred to as “Compound (1a)”) can be produced by, forexample, the process shown in Reaction Scheme 2.

wherein R¹, R², R³ and A¹ are as defined in Formula (1).

Compound (1a) is produced by reacting Compound (4) or a reactivederivative thereof at the carboxy group, with Compound (5) or a reactivederivative thereof at the amino or imino group.

Preferable examples of reactive derivatives of Compound (4) include acidhalides, acid anhydrides, activated amides, activated esters, etc.Preferable examples of reactive derivatives include acid chlorides; acidazides; dialkylphosphoric acids, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphoric acid, phosphoric acidhalides, and other substituted phosphoric acids, dialkylphosphorousacid, sulfurous acid, thiosulfuric acid, sulfuric acid, methanesulfonicacid, and other sulfonic acids, acetic acid, propionic acid, butyricacid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, and other aliphaticcarboxylic acids, and mixed acid anhydrides with acids such as benzoicacid or other aromatic acids; symmetrical acid anhydrides; activatedamides with imidazole, 4-substituted imidazole, dimethylpyrazole,triazole or tetrazole; cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenylester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenylester, mesylphenyl ester, and other activated esters, esters withN,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazol,and other N-hydroxy compounds; etc. Such reactive derivatives can beselected as desired, according to the type of Compound (4) used.

When using Compound (4) in the form of a free acid or a salt thereof inthe above reaction, it is preferable to perform the reaction in thepresence of condensing agent(s). A wide variety of condensing agentsknown in this field can be used, including, for example,N,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diethylcarbodiimide; N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide and hydrochloridesthereof; N,N′-carbonylbis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene,1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; phosphoryl diphenyl azide; thionyl chloride;oxalyl chloride; ethyl chloroformate, isopropyl chloroformate, and otherlower alkyl haloformates; triphenylphosphine;2-ethyl-7-hydroxybenzisooxazolium salt;2-ethyl-5-(m-sulfophenyl)isooxazolium hydroxide inner salts;hexafluorophosphoric acidbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium;1-(p-chlorobenzene-sulfonyloxy)-6-chloro-1H-benzotriazol; so-calledVilsmeier reagents prepared by reacting N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; and the like. It is more preferable to perform thereaction in the presence of such condensing agent(s) and activeesterifying agent(s) such as N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxy-1H-benzotriazol, or the like.

Preferable examples of reactive derivatives of Compound (5) includeSchiff base imino- or enamine-type tautomers produced by reactingCompound (5) with carbonyl compounds such as aldehydes, ketones, etc.;silyl derivatives produced by reacting Compound (5) with silyl compoundssuch as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea, etc.; derivatives produced by reacting Compound(5) with phosphorus trichloride, phosgene, etc.; and the like.

The reaction is usually carried out in a known solvent that does notadversely affect the reaction. Such solvents include, for example,water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,ethylene glycol, and other alcohol solvents; acetone, methyl ethylketone, and other ketone solvents; tetrahydrofuran, dioxane, diethylether, diisopropyl ether, diglyme, and other ether solvents; methylacetate, ethyl acetate, and other ester solvents; acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, and other aprotic polarsolvents; n-pentane, n-hexane, n-heptane, cyclohexane, and otherhydrocarbon solvents; methylene chloride, ethylene chloride, and otherhalogenated hydrocarbon solvents; other organic solvents; and mixedsolvents thereof.

The reaction may be performed in the presence of base(s). A wide varietyof known inorganic and organic bases are usable. Inorganic basesinclude, for example, alkali metals (e.g., sodium, potassium, etc.),alkali metal hydrogencarbonates (e.g., lithium hydrogencarbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate etc.), alkali metalhydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g.,lithium carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, etc.), alkali metal lower alkoxides (e.g., sodium methoxide,sodium ethoxide, etc.), and alkali metal hydrides (e.g., sodium hydride,potassium hydride, etc.). Organic bases include, for example,trialkylamines [e.g., trimethylamine, triethylamine,N-ethyldiisopropylamine, etc.], pyridine, quinoline, piperidine,imidazole, picoline, dimethylaminopyridine, dimethylaniline,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases areliquid, they can also be used as solvents.

Such bases can be used singly or in combination.

The amount of base(s) is usually 0.1 to 10 moles, and preferably 0.1 to3 moles, per mole of Compound (4).

The proportion of Compound (4) to Compound (5) in Reaction Scheme 1 isusually at least 1, and preferably about 1 to about 5 mol of the formerper mol of the latter.

The reaction temperature is not limited, and the reaction can usually beperformed with cooling, at room temperature, or with heating. It issuitable to perform the reaction in a temperature range from roomtemperature to 100° C., for 30 minutes to 30 hours, and preferably for30 minutes to 5 hours.

In the above reaction, Compound (4) for use as a starting material is aneasily available known compound. Compound (5) encompasses novelcompounds. A production process for Compound (5) is describedhereinafter (Reaction Scheme 10).

Among the oxazole compounds represented by Formula (1), those in which Wis a divalent group represented by —Y¹-A¹- wherein Y¹ is —C(═O)— and A¹is a lower alkylene group having one lower alkoxycarbonyl group(hereinafter referred to as “Compound (1b)”) can be produced, forexample, by the process shown in Reaction Scheme 3.

wherein R¹ and R² are as defined in Formula (1), R⁷ and R⁸ are eachindependently a lower alkyl group, and A^(1a) is a C₁₋₅ alkylene group.

The —COOR⁸ group in Formula (1b) is the same as the lower alkoxycarbonylgroup defined as a substituent of A¹ in Formula (1). The lower alkylgroup represented by R⁷ may be the same as the lower alkyl group asdefined above.

Examples of the C₁₋₅ alkylene group represented by A^(1a) includeethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene,1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene,pentamethylene, and other C₁₋₅ straight- or branched-chain alkylenegroups.

Compound (1b) is produced by reacting Compound (6) with Compound (7).

The reaction is usually performed in a known solvent that does notadversely affect the reaction. Such solvents include, for example,water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,ethylene glycol, and other alcohol solvents; acetone, methyl ethylketone, and other ketone solvents; tetrahydrofuran, dioxane, diethylether, dimethoxyethane, diglyme, and other ether solvents; methylacetate, ethyl acetate, and other ester solvents; acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, andother aprotic polar solvents; methylene chloride, ethylene chloride, andother halogenated hydrocarbon solvents; other organic solvents; andmixed solvents thereof.

The reaction can usually be performed in the presence of suitablebase(s). A wide variety of known inorganic and organic bases are usable.Inorganic bases include, for example, alkali metals (e.g., lithium,sodium, potassium, etc.), alkali metal hydrogencarbonates (e.g., lithiumhydrogencarbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.), alkali metal carbonates (e.g., lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, etc.), alkali metallower alkoxides (e.g., sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium tert-butoxide, sodium tert-pentoxide, etc.),alkali metal hydrides (e.g., sodium hydride, potassium hydride, etc.),and the like. Organic bases include, for example, trialkylamines (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases areliquid, they can also be used as solvents. Such bases can be used singlyor in combination.

The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mol of Compound (6).

The proportion of Compound (6) to Compound (7) is usually at least 1mol, and preferably about 1 to about 5 mol of the former, per mol of thelatter.

The reaction temperature is not limited, and the reaction can usually beperformed with cooling, at room temperature, or with heating. It issuitable to perform the reaction in a temperature range from roomtemperature to 150° C., for 30 minutes to 60 hours, and preferably 1 to30 minutes.

Compound (6) used as a starting material in the above reaction is aneasily available known compound. Compound (7) encompasses novelcompounds. A production process for Compound (7) is describedhereinafter (Reaction Scheme 11).

Among the oxazole compounds represented by Formula (1), those in which Wis a divalent group represented by —Y¹-A¹- wherein A¹ is a loweralkylene group (hereinafter referred to as “Compound (1d)”) are producedfrom the corresponding compounds in which A^(l) is a lower alkylenegroup having lower alkoxycarbonyl group(s) (hereinafter referred to as“Compound (1c)”), by the process shown in Reaction Scheme 4.

wherein R¹, R² and Y¹ are as defined in Formula (1), A^(1b) is a loweralkylene group having lower alkoxycarbonyl group(s), and A^(1c) is alower alkylene group.

Compound (1d) is produced by subjecting Compound (1c) tohydrolysis-decarboxylation.

The reaction is usually performed in a known solvent that does notadversely affect the reaction. Such solvents include, for example,water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,ethylene glycol, and other alcohol solvents; acetone, methyl ethylketone, and other ketone solvents; tetrahydrofuran, dioxane, diethylether, dimethoxyethane, diglyme, and other ether solvents; methylacetate, ethyl acetate, and other ester solvents; acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, andother aprotic polar solvents; methylene chloride, ethylene chloride, andother halogenated hydrocarbon solvents; other organic solvents; andmixed solvents thereof.

The hydrolysis-decarboxylation of Compound (1c) is usually performedunder acidic conditions. For example, an acid is added to a suspensionor solution of Compound (1c) in a suitable solvent, and the resultingmixture is stirred at 0 to 120° C. to carry out thehydrolysis-decarboxylation.

Examples of usable acids include trifluoroacetic acid, acetic acid, andother organic acids, hydrochloric acid, bromic acid, hydrobromic acid,sulfuric acid, and other inorganic acids, etc. Among such organic acids,organic acids can also be used as reaction solvents.

The amount of acid(s) is usually 0.5 to 30 mol, and preferably 0.5 to 10mol, per mol of Compound (1c).

The reaction temperature is usually 0 to 120° C., and preferably roomtemperature to 110° C. The reaction time is usually 30 minutes to 24hours, preferably 30 minutes to 12 hours, and more preferably 1 to 8hours.

Among the oxazole compounds represented by Formula (1), those in whichR¹ is a phenyl group substituted on the phenyl ring with hydroxygroup(s) (hereinafter referred to as “Compound (1f)”) are produced fromthe corresponding compounds in which R¹ is a phenyl group substituted onthe phenyl ring with protected hydroxy group(s) (hereinafter referred toas “Compound (1e)”), by the process shown in Reaction Scheme 5.

wherein R² and W are as defined in Formula (1); R⁹ is a protectedhydroxy group; R¹⁰ is the same group as the substituent (1-2), (1-3),(1-4), (1-5), (1-6), (1-7), (1-8), (1-9) or (1-10) of the aryl grouprepresented by R¹ in Formula (1); m is 1 to 5; q is 0 to 4; m R⁹s may bethe same or different; and q R¹⁰s may be the same or different; with theproviso that m+q≤5.

Compound (1f) can be produced by subjecting Compound (1e) to anelimination reaction of the hydroxy protecting group(s).

The elimination reaction can be carried out by hydrolysis,hydrogenolysis, or other conventional methods.

The reaction is usually performed in a known solvent that does notadversely affect the reaction. Such solvents include, for example,water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,ethylene glycol, and other alcohol solvents; acetone, methyl ethylketone, and other ketone solvents; tetrahydrofuran, dioxane, diethylether, dimethoxyethane, diglyme, and other ether solvents; methylacetate, ethyl acetate, and other ester solvents; acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, andother aprotic polar solvents; methylene chloride, ethylene chloride, andother halogenated hydrocarbon solvents; and other organic solvents.

(i) Hydrolysis:

Hydrolysis is preferably carried out in the presence of base(s) oracid(s) (including Lewis acids).

A wide variety of known inorganic and organic bases are usable.Preferable examples of inorganic bases include alkali metals (e.g.,sodium, potassium, etc.), alkaline earth metals (e.g., magnesium,calcium, etc.), hydroxides, carbonates and hydrogencarbonates thereof,etc. Preferable examples of organic bases include trialkylamines (e.g.,trimethylamine, triethylamine, etc.), picoline,1,5-diazabicyclo[4,3,0]non-5-ene, etc.

A wide variety of known organic and inorganic acids are usable.Preferable organic acids include, for example, formic acid, acetic acid,propionic acid, and other fatty acids; trichloroacetic acid,trifluoroacetic acid, and other trihaloacetic acids; and the like.Preferable inorganic acids include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide,etc. Examples of Lewis acids include boron trifluoride ether complexes,boron tribromide, aluminium chloride, ferric chloride, etc.

When using a trihaloacetic acid or Lewis acid, it is preferable to carryout hydrolysis in the presence of a cation scavenger (e.g., anisole,phenol, etc.).

The amount of base(s) or acid(s) is not limited as long as it is anamount necessary for hydrolysis.

The reaction temperature is usually 0 to 120° C., preferably roomtemperature to 100° C., and more preferably room temperature to 80° C.The reaction time is usually 30 minutes to 24 hours, preferably 30minutes to 12 hours, and more preferably 1 to 8 hours.

(ii) Hydrogenolysis:

Hydrogenolysis can be carried out by a wide variety of known methodsincluding, for example, chemical reduction, catalytic reduction, etc.

Examples of suitable reducing agents for chemical reduction includehydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminiumhydride, sodium borohydride, sodium cyanoborohydride, etc.); andcombinations of metals (e.g., tin, zinc, iron, etc.) or metalliccompounds (e.g., chromium chloride, chromium acetate, etc.), withorganic or inorganic acids (e.g., formic acid, acetic acid, propionicacid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

Examples of suitable catalysts for catalytic reduction include platinumcatalysts (e.g., platinum plates, spongy platinum, platinum black,colloidal platinum, platinum oxide, platinum wires, etc.), palladiumcatalysts (e.g., spongy palladium, palladium black, palladium oxide,palladium carbon, palladium/barium sulfate, palladium/barium carbonate,etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raneynickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt,etc.), iron catalysts (e.g., reduced iron and the like), etc.

When such acids used for chemical reduction are liquid, they can also beused as solvents.

The amounts of reducing agent for chemical reduction and catalyst forcatalytic reduction are not limited and may be conventional amounts.

The reaction temperature is usually 0 to 120° C., preferably roomtemperature to 100° C., and more preferably room temperature to 80° C.The reaction time is usually 30 minutes to 24 hours, preferably 30minutes to 10 hours, and more preferably 30 minutes to 4 hours.

Among the oxazole compounds represented by Formula (1), those in whichR¹ is a phenyl group substituted on the phenyl ring with R¹¹O— group(s)(hereinafter referred to as “Compound (1 g)”) are produced from Compound(1f), by the process shown in Reaction Scheme 6.

wherein R² and W are as defined in Formula (1); R¹⁰, m and q are asdefined above; X¹ is a halogen atom or a group that undergoes the samesubstitution reaction as that of a halogen atom; R¹¹O is the same groupas the substituent (1-2), (1-3), (1-4), (1-5), (1-6), (1-7), (1-8),(1-9) or (1-10) of the aryl group represented by R¹ in Formula (1); andm R¹¹Os may be the same or different.

In Compound (8), the halogen atom represented by X¹ is a fluorine atom,chlorine atom, bromine atom, or iodine atom.

Examples of the group that undergoes the same substitution reaction asthat of a halogen atom, the group being represented by X¹, include loweralkanesulfonyloxy groups, arylsulfonyloxy groups, aralkylsulfonyloxygroups, etc.

Specific examples of lower alkanesulfonyloxy groups includemethanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy,n-propanesulfonyloxy, n-butanesulfonyloxy, tert-butanesulfonyloxy,n-pentanesulfonyloxy, n-hexanesulfonyloxy, and other C₁₋₆ straight- orbranched-chain alkanesulfonyloxy groups, and the like.

Arylsulfonyloxy groups include, for example, phenylsulfonyloxy,naphthylsulfonyloxy, etc. The phenyl ring of such arylsulfonyloxy groupsmay have, for example, 1 to 3 substituents selected from the groupconsisting of C₁₋₆ straight- or branched-chain alkyl groups, C₁₋₆straight- or branched-chain alkoxy groups, nitro groups, and halogenatoms. Specific examples of such arylsulfonyloxy groups includephenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, etc. Specificexamples of naphthylsulfonyloxy groups include α-naphthylsulfonyloxy,β-naphthylsulfonyloxy, etc.

Aralkylsulfonyloxy groups include, for example, phenyl-substituted C₁₋₆straight- or branched-chain alkylsulfonyloxy groups which may have, onthe phenyl ring, 1 to 3 substituents selected from the group consistingof C₁₋₆ straight- or branched-chain alkyl groups, C₁₋₆ straight- orbranched-chain alkoxy groups, nitro groups, and halogen atoms;naphthyl-substituted C₁₋₆ straight- or branched-chain alkylsulfonyloxygroups; etc. Specific examples of phenyl-substituted alkylsulfonyloxygroups as mentioned above include benzylsulfonyloxy,2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy,2-methylbenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy,4-nitrobenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, etc. Specificexamples of naphthyl-substituted alkylsulfonyloxy groups as mentionedabove include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy,etc.

Compound (1 g) is produced by reacting Compound (1f) with Compound (8),or by reacting Compound (1f) with Compound (8′).

The reaction of Compound (1f) with Compound (8) is described below.

The reaction of Compound (1f) with Compound (8) is usually performed ina known solvent that does adversely affect the reaction. Such solventsinclude, for example, water; methanol, ethanol, isopropanol, n-butanol,trifluoroethanol, ethylene glycol, and other alcohol solvents; acetone,methyl ethyl ketone, and other ketone solvents; tetrahydrofuran,dioxane, diethyl ether, diglyme, and other ether solvents; methylacetate, ethyl acetate, and other ester solvents; acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, and other aprotic polarsolvents; methylene chloride, ethylene chloride, and other halogenatedhydrocarbon solvents; other organic solvents; mixed solvents thereof;etc.

The reaction of Compound (1f) with Compound (8) is usually carried outin the presence of base(s). Usable bases include known inorganic andorganic bases. Inorganic bases include, for example, alkali metals(e.g., sodium, potassium, etc.), alkali metal hydrogencarbonates (e.g.,lithium hydrogencarbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.), alkali metal carbonates (e.g., lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, etc.), alkali metallower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), alkalimetal hydrides (e.g., sodium hydride, potassium hydride, etc.), and thelike. Organic bases include, for example, trialkylamines (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases areliquid, they can also be used as solvents. Such bases can be used singlyor in combination.

The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mol of Compound (1f).

When performing the above reaction, alkali metals such as potassiumiodide, sodium iodide, etc. can be added as reaction accelerators to thereaction system, as required.

The proportion of Compound (1f) to Compound (8) is usually at least 1mol, and preferably about 1 to about 5 mol of the latter, per mol of theformer.

The reaction temperature is not limited, and the reaction can usually beperformed with cooling, at room temperature, or with heating. It issuitable to perform the reaction at about room temperature for 1 to 30hours.

Next, the reaction of Compound (1f) with Compound (8′) is described.

The reaction of Compound (1f) with Compound (8′) is usually performed ina known solvent that does not adversely affect the reaction. Suchsolvents include, for example, water; methanol, ethanol, isopropanol,n-butanol, trifluoroethanol, ethylene glycol, and other alcoholsolvents; acetone, methyl ethyl ketone, and other ketone solvents;tetrahydrofuran, dioxane, diethyl ether, diglyme, and other ethersolvents; methyl acetate, ethyl acetate, and other ester solvents;acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and otheraprotic polar solvents; benzene, toluene, xylene, and other aromatichydrocarbon solvents; methylene chloride, ethylene chloride, and otherhalogenated hydrocarbon solvents; other organic solvents; mixed solventsthereof; etc.

The reaction is usually performed in the presence of dialkylazodicarboxylate(s) such as diisopropyl azodicarboxylate, diethylazodicarboxylate, etc., and phosphine ligand(s) such as triphenylphosphine, tri(n-butyl)phosphine, etc. The amount of dialkylazodicarboxylate(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mole of Compound (1f). The amount of phosphine ligand(s) isusually 0.5 to 10 mol, and preferably 0.5 to 6 mol, per mole of Compound(1f).

The reaction of Compound (1f) with Compound (8′) can be carried out inthe presence of suitable base(s). A wide variety of known inorganic andorganic bases are usable. Inorganic bases include, for example, alkalimetals (e.g., sodium, potassium, etc.), alkali metal hydrogencarbonates(e.g., lithium hydrogencarbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.), alkali metal carbonates (e.g., lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, etc.), alkali metallower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), alkalimetal hydrides (e.g., sodium hydride, potassium hydride, etc.), and thelike. Organic bases include, for example, trialkylamines (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases areliquid, they can also be used as solvents. Such bases can be used singlyor in combination.

The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mol of Compound (1f).

The proportion of Compound (1f) to Compound (8′) is usually at least 1mol, and preferably about 1 to about 5 mol of the latter, per mol of theformer.

The reaction temperature is not limited, and the reaction can usually beperformed with cooling, at room temperature, or with heating. It issuitable to perform the reaction at about room temperature for 1 to 30hours.

Compounds (8) and (8′) used as starting materials in the above reactionare easily available known compounds.

Among the oxazole compounds represented by Formula (1), those in which Wis a divalent group represented by —Y¹-A¹- wherein Y¹ is —C(═O) and A¹is a lower alkenylene group (hereinafter referred to as “Compound (1h)”)can be produced by, for example, the process shown in Reaction Scheme 7.

wherein R¹ and R² are as defined in Formula (1), and A^(1d) is a C₂₋₄alkenylene group, a C₁₋₄ alkylene group, or a direct bond.

Each of the C₂₋₄ alkenyl group and C₁₋₄ alkylene group may be straight-or branched-chain. —CH═CH-A^(1d) corresponds to the lower alkenylenegroup represented by A¹ in Formula (1).

Compound (1h) is produced by reacting Compound (9) with Compound (10).

The reaction is usually performed in a known solvent that does notadversely affect the reaction. Such solvents include, for example,water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,ethylene glycol, and other alcohol solvents; acetone, methyl ethylketone, and other ketone solvents; tetrahydrofuran, dioxane, diethylether, dimethoxyethane, diglyme, and other ether solvents; methylacetate, ethyl acetate, and other ester solvents; acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, andother aprotic polar solvents; methylene chloride, ethylene chloride, andother halogenated hydrocarbon solvents; other organic solvents; mixedsolvents thereof; etc.

The reaction can be performed in the presence of base(s). A wide varietyof known inorganic and organic bases are usable. Inorganic basesinclude, for example, alkali metals (e.g., lithium, sodium, potassium,etc.), alkali metal hydrogencarbonates (e.g., lithium hydrogencarbonate,sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkalimetal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g.,lithium carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, etc.), alkali metal lower alkoxides (e.g., sodium methoxide,sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc.),alkali metal hydrides (e.g., sodium hydride, potassium hydride, etc.),and the like. Organic bases include, for example, trialkylamines (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases areliquid, they can also be used as solvents. Such bases can be used singlyor in combination.

The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mol of Compound (9).

The proportion of Compound (9) to Compound (10) is usually at least 1mol, and preferably about 1 to about 5 mol of the latter, per mol of theformer.

The reaction temperature is not limited, and the reaction can usually beperformed with cooling, at room temperature, or with heating. It issuitable to perform the reaction in a temperature range from roomtemperature to 150° C., for 30 minutes to 60 hours, and preferably for 1to 30 hours.

Compound (9) used as a starting material in the above reaction is aneasily available known compound. Compound (10) used as a startingmaterial in the above reaction can be produced by the process shown inReaction Scheme 12.

Among the oxazole compounds represented by Formula (1), those in which Wis a divalent group represented by —Y¹-A¹- wherein A¹ is a loweralkylene group (hereinafter referred to as “Compound (1j)”) can beproduced from compounds in which A¹ is a lower alkenylene group(hereinafter referred to as “Compound (1i)”), by the process shown inReaction Scheme 8.

wherein R¹ and R² are as defined in Formula (1), Y¹ is as defined above,A^(1e) is a lower alkenylene group, and A^(1f) is a lower alkylenegroup.

Compound (1j) is produced by subjecting Compound (1i) to hydrogenolysis.

The reaction is performed under the same reaction conditions as of thereaction shown in Reaction Scheme 5 for the hydrogenolysis of Compound(1e) to obtain Compound (1f). Therefore, the same reagent(s) andreaction conditions (e.g., solvent, reaction temperature, etc.) as thoseused in the hydrogenolysis shown in Reaction Scheme 5 can be used in theabove reaction.

wherein R² and W are as defined in Formula (1), and X is as definedabove.

The halogenation reaction of Compound (11) is performed in a suitablesolvent in the presence of a halogenating agent. Usable halogenatingagents include, for example, Br₂, Cl₂, and other halogen molecules;iodine chloride, sulfuryl chloride, cupric bromide, and other coppercompounds; N-bromosuccinimide, N-chlorosuccinimide, and otherN-halosuccinimides, etc. Usable solvents include, for example,dichloromethane, dichloroethane, chloroform, carbon tetrachloride, andother halogenated hydrocarbons; acetic acid, propionic acid, and otherfatty acids; carbon disulfide; etc. The amount of halogenating agent isusually 1 to 10 mol, and preferably 1 to 5 mol, per mol of Compound(11). The reaction is usually complete at 0° C. to the boiling pointtemperature of the solvent, and preferably about 0 to about 100° C., inabout 5 minutes to about 20 hours.

Among Compounds (5) for use as starting materials, those in which R³ isa hydrogen atom (hereinafter referred to as “Compound (5a)”) areproduced by the process shown in Reaction Scheme 10.

wherein R¹ and A¹ are as defined in Formula (1), X² and X³ are eachindependently a halogen atom or a group that undergoes the samesubstitution reaction as that of a halogen atom as mentioned above, andM is an alkali metal.

Examples of the alkali metal represented by M include sodium, potassium,etc.

Compound (14) is produced by reacting Compound (12) with Compound (13).

The reaction of Compound (12) with Compound (13) is usually performed ina known solvent that does not adversely affect the reaction. Suchsolvents include, for example, water; methanol, ethanol, isopropanol,n-butanol, trifluoroethanol, ethylene glycol, and other alcoholsolvents; acetone, methyl ethyl ketone, and other ketone solvents;tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, andother ether solvents; methyl acetate, ethyl acetate, and other estersolvents; acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone, and other aprotic polar solvents; methylenechloride, ethylene chloride, and other halogenated hydrocarbon solvents;and other organic solvents; etc.

The proportion of Compound (12) to Compound (13) is usually at least 1mol, and preferably about 1 to about 5 mol of the latter, per mol of theformer. The reaction of Compound (12) with Compound (13) is performed bycontinuing stirring usually in a temperature range from room temperatureto 200° C., and preferably from room temperature to 150° C., usually for30 minutes to 60 hours, and preferably 1 to 30 hours.

Compound (16) is produced by reacting Compound (15) with Compound (14).

The reaction of Compound (15) with Compound (14) is usually performed ina known solvent that does not adversely affect the reaction. Suchsolvents include, for example, water; methanol, ethanol, isopropanol,n-butanol, trifluoroethanol, ethylene glycol, and other alcoholsolvents; acetone, methyl ethyl ketone, and other ketone solvents;tetrahydrofuran, dioxane, diethyl ether, diglyme, and other ethersolvents; methyl acetate, ethyl acetate, and other ester solvents;acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and otheraprotic polar solvents; methylene chloride, ethylene chloride, and otherhalogenated hydrocarbon solvents; other organic solvents; mixturesthereof; etc.

When performing the reaction of Compound (15) with Compound (14), alkalimetal iodides such as potassium iodide, sodium iodide, etc. can be addedas reaction accelerators to the reaction system, as required.

The proportion of Compound (15) to Compound (14) is usually at least 1mol, and preferably about 1 to about 5 mol of the latter, per mol of theformer.

The temperature of the reaction of Compound (15) with Compound (14) isnot limited, and the reaction can usually be performed with cooling, atroom temperature, or with heating. It is suitable to perform thereaction in a temperature range from room temperature to 100° C., for 1to 60 hours, and preferably for 1 to 30 hours.

In the reaction of Compound (15) with Compound (14), phthalimide can beused in place of Compound (15) and the reaction may be performed in thepresence of base(s). A wide variety of known inorganic and organic basesare usable. Examples of inorganic bases include alkali metals (e.g.,lithium, sodium, potassium, etc.), alkali metal hydrogencarbonates(e.g., lithium hydrogencarbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.), alkali metal carbonates (e.g., lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, etc.), alkali metallower alkoxides (e.g., sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium tert-butoxide, etc.), alkali metal hydrides (e.g.,sodium hydride, potassium hydride, etc.), and the like. Organic basesinclude, for example, trialkylamines (e.g., trimethylamine,triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline,piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.

The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mol of Compound (14).

Compound (5a) is produced by reacting Compound (16) with Compound (17).

The reaction of Compound (16) with Compound (17) is usually performed ina known solvent that does not adversely affect the reaction. Suchsolvents include, for example, water; methanol, ethanol, isopropanol,n-butanol, trifluoroethanol, ethylene glycol, and other alcoholsolvents; acetone, methyl ethyl ketone, and other ketone solvents;tetrahydrofuran, dioxane, diethyl ether, diglyme, and other ethersolvents; methyl acetate, ethyl acetate, and other ester solvents;acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and otheraprotic polar solvents; methylene chloride, ethylene chloride, and otherhalogenated hydrocarbon solvents; other organic solvents; mixturesthereof; etc.

The proportion of Compound (16) to Compound (17) is usually at least 1mol, and preferably about 1 to about 5 mol of the latter, per mol of theformer.

The temperature of the reaction of Compound (16) with Compound (17) isnot limited, and the reaction can usually be performed with cooling, atroom temperature, or with heating. It is suitable to perform thereaction at about room temperature for 1 to 30 hours.

wherein R¹ is as defined in Formula (1); R⁸ and A^(1a) are as definedabove; X⁴ is a halogen atom or a group that undergoes the samesubstitution reaction as that of a halogen atom as mentioned above; andR¹² is a lower alkyl group.

Compound (20) is produced by reacting Compound (18) with Compound (19).

The reaction of Compound (18) with Compound (19) is usually performed ina known solvent that does not adversely affect the reaction. Suchsolvents include, for example, water; methanol, ethanol, isopropanol,n-butanol, trifluoroethanol, ethylene glycol, and other alcoholsolvents; acetone, methyl ethyl ketone, and other ketone solvents;tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, andother ether solvents; methyl acetate, ethyl acetate, and other estersolvents; acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone, and other aprotic polar solvents; methylenechloride, ethylene chloride, and other halogenated hydrocarbon solvents;other organic solvents; mixtures thereof; etc.

The reaction of Compound (18) with Compound (19) can usually beperformed in the presence of suitable base (s). A wide variety of knowninorganic and organic bases are usable. Inorganic bases include, forexample, alkali metals (e.g., lithium, sodium, potassium, etc.), alkalimetal hydrogencarbonates (e.g., lithium hydrogencarbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metalhydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g.,lithium carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, etc.), alkali metal lower alkoxides (e.g., sodium methoxide,sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc.),alkali metal hydrides (e.g., sodium hydride, potassium hydride, etc.),and the like. Organic bases include, for example, trialkylamines (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases areliquid, they can also be used as solvents.

Such bases can be used singly or in combination.

The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mol of Compound (18).

The proportion of Compound (18) to Compound (19) in Reaction Scheme 11is usually at least 1 mol, and preferably about 1 to about 5 mol of thelatter, per mol of the former.

The reaction temperature is not limited, and the reaction can usually beperformed with cooling, at room temperature, or with heating. It issuitable to perform the reaction in a temperature range from roomtemperature to 100° C., for 30 minutes to 60 hours, and preferably 1 to30 hours.

Compound (7) is produced by subjecting Compound (20) tohydrolysis-decarboxylation. The hydrolysis-decarboxylation of Compound(20) can be carried out by the process shown in Reference Example 48given hereinafter, a process similar thereto, the process shown inReaction Scheme 4 above, or a process similar thereto.

wherein R¹ is as defined in Formula (1), and X² and Aid are as definedabove.

Compound (10) is produced by subjecting Compound (21) to an oxidationreaction. The reaction can be carried out by the process shown inReference Example 64 given hereinafter, or a process similar thereto,and is performed in the presence of a known solvent that does notadversely affect the reaction. Such solvents include, for example,water; methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,ethylene glycol, and other alcohol solvents; acetone, methyl ethylketone, and other ketone solvents; tetrahydrofuran, dioxane, diethylether, diglyme, and other ether solvents; methyl acetate, ethyl acetate,and other ester solvents; acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, and other aprotic polar solvents; methylene chloride,ethylene chloride, and other halogenated hydrocarbon solvents; otherorganic solvents; mixtures thereof; etc.

The reaction is usually performed using oxidizing agent(s) such asdimethyl sulfoxide, hexamethylenetetramine, triethylamine-N-oxide, etc.

If necessary, the reaction can be performed in the presence of suitablebase(s). A wide variety of known inorganic and organic bases are usable.Inorganic bases include, for example, alkali metals (e.g., sodium,potassium, etc.), alkali metal hydrogencarbonates (e.g., lithiumhydrogencarbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.), alkali metal carbonates (e.g., lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, etc.), alkali metallower alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), alkalimetal hydrides (e.g., sodium hydride, potassium hydride, etc.), and thelike. Organic bases include, for example, trialkylamines (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. When such bases areliquid, they can also be used as solvents. Such bases can be used singlyor in combination.

The amount of oxidizing agent is usually 0.5 to 10 mol, and preferably0.5 to 6 mol, per mol of Compound (21).

The amount of base(s) is usually 0.5 to 10 mol, and preferably 0.5 to 6mol, per mol of Compound (21).

When performing the above reaction, alkali metals such as potassiumiodide, sodium iodide, etc. can be added as reaction accelerators to thereaction system, as required.

The reaction temperature is not limited, and the reaction can usually beperformed with cooling, at room temperature, or with heating. It issuitable to perform the reaction in a temperature range from roomtemperature to 120° C. for 30 minutes to 30 hours.

The starting material compounds used in the above reaction schemes maybe suitable salts, and the objective compounds obtained by the abovereactions may be in the form of suitable salts.

Each of the objective compounds obtained according to the above reactionschemes can be isolated and purified from the reaction mixture by, forexample, cooling the reaction mixture, separating the crude reactionproduct from the reaction mixture by an isolation procedure such asfiltration, concentration, extraction and/or other isolation procedures,and then purifying the crude reaction product by column chromatography,recrystallization and/or other conventional purification procedures.

Suitable salts of Compound (1) are pharmaceutically acceptable saltsincluding, for example, metal salts such as alkali metal salts (e.g.,sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g.,calcium salt, magnesium salt, etc.), etc., ammonium salts, alkali metalcarbonates (e.g., lithium carbonate, potassium carbonate, sodiumcarbonate, cesium carbonate, etc.), alkali metal hydrogencarbonates(e.g., lithium hydrogencarbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.), and other salts of inorganic bases; tri(lower)alkylamines (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-(lower)alkylmorpholines (e.g., N-methylmorpholine andthe like), DBN, DBU, DABCO, and other salts of organic bases;hydrochlorides, hydrobrmides, hydroiodides, sulfates, nitrates,phosphates, and other salts of inorganic acids; formates, acetates,propionates, oxalates, malonates, succinates, fumarates, maleates,lactates, malates, citrates, tartrates, citrates, carbonates, picrates,methanesulfonates, ethanesulfonates, p-toluenesulfonates, glutamates,and other salts of inorganic acids; etc.

The starting material compounds and objective compounds represented bythe formulae in the above reaction schemes encompass solvates (e.g.hydrates, ethanolates, etc.). Preferable solvates include hydrates.

The compounds represented by Formula (1) of the present invention ofcourse encompass isomers such as geometrical isomers, stereoisomer,optical isomers, etc.

Drug Efficacy and Use

Compounds represented by formula (1), optically active isomers thereof,and salts thereof (hereinafter referred to as “compounds of the presentinvention”) have a specific inhibitory action against PDE4, and arehence useful as active ingredients for a PDE4 inhibitor.

Further, due to their PDE4-specific inhibitory action, the compounds ofthe invention can be useful as active ingredients of pharmaceuticalcompositions used as prophylactic and therapeutic agents for variousdiseases. More specifically, diseases efficiently preventable andtreatable by the PED4-specific inhibitory action include variousorigin-generated acute and chronic (in particular, inflammatory andallergen induced) respiratory tract diseases (e.g. bronchial asthma,chronic obstructive pulmonary disease, etc.); dermatoses (in particular,hyperplastic, inflammatory, and allergic diseases) (e.g. psoriasis(vulgaris), toxic and allergic contact eczema, atopic dermatitis,alopecia areata, and other hyperplastic, inflammatory and allergicdermatoses); nervous function abnormality diseases such as learning,memory, and/or cognition disorders associated with Altzheimer's andPerkinson's diseases; diseases associated with mental functionabnormality (e.g. manic-depressive psychosis, schizophrenia, anxietydisorder, etc.); systemic and local arthritic disorders (e.g. kneeosteoarthritis, articular rheumatism, etc.); gastrointestinal diffuseinflammation (e.g. Crohn's disease and ulcerative colitis); allergicand/or chronic immune-mediated inflammatory diseases in the upperrespiratory tract (cavum pharynges, nose) and its vicinity (sinuses,eyes) (e.g. allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,allergic conjunctivitis), and the like. Among these, the compounds areparticularly effective in preventing and treating atopic dermatitis,making this diseases a suitable target disease for prevention andtreatment.

When used as a PDE4 inhibitor or as prophylactic or therapeutic agentfor the above-mentioned various diseases, the compounds of the inventioncan be used as oral agents, injectable solutions, external preparations,and the like.

For oral agents, for example, the compounds may be prepared in any formssuch as powders, tablets, granules, capsules, syrups, films, troches,liquids, etc. Such oral agents can contain pharmaceutically acceptablebase materials and carriers, and further optionally contain as necessarybinders, disintegrators, lubricants, humectants, buffers, preservatives,fragrances, and the like.

For injectable solutions, the compounds may be prepared in the form ofsolutions dissolved in physiological saline, grape sugar solutions andthe like, or aqueous suspensions.

For external preparations, the compounds may be prepared in any forms,for example, such as liquid medicines, oily medicines, lotions,liniments, emulsions, suspensions, creams, ointments, etc. Such externalpreparations can optionally contain various carriers, base materials,and additives as typically used in external preparations, and examplesinclude water, oils, surfactants, solubilized components, emulsifiers,colorants (dyes and pigments), fragrances, preservatives, disinfectants,thickeners, antioxidants, chelators, pH adjusting agents, deodorants,etc.

When used as a PDE4 inhibitor, or as prophylactic or therapeutic agentfor the aforementioned various diseases, effective dose and number ofdoses a day of the compound vary depending on the purpose of use, kindof compound used, the age, weight, symptoms, etc. of a subject, andcannot be uniformly prescribed. For example, the inhibitor or agent canbe administered in a dose of 0.1 to 1000 mg of the compound(s) of thepresent invention per day per adult, and may be administered in one toseveral portions a day.

Further, in light of other viewpoints, the present invention provides amethod for treating or preventing the aforementioned various diseasescomprising the step of administrating an effective dose of thecompound(s) of the invention to a mammal, such as a human.

Furthermore, since the compounds of the present invention haveinhibitory action against TNF-α production, they are useful as activeingredients for TNF-α production suppressants. Diseases that benefitfrom such TNF-α production inhibitory action include those efficientlypreventable and treatable by the aforementioned PDE4-specific inhibitoryaction. Preparation forms, administration routes and doses of TNF-αproduction suppressant containing compounds of the invention are thesame as those of the aforementioned PDE4 inhibitor and prophylactic andtherapeutic agents.

EFFECT OF THE INVENTION

The compounds of the present invention have an inhibitory actionspecific against PDE4, and are hence useful as active ingredients for aPDE 4 inhibitors.

Due to their specific PDE4 inhibitory activity, the compounds of theinvention are further useful as prophylactic and therapeutic agents forvarious diseases including atopic dermatitis.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in more detail below with referenceto Examples; however, the present invention is not limited thereto.

Reference Example 1

A 25 g quantity of isovanillic acid was suspended in 250 ml of methanol,and 1.5 g of p-toluenesulfonic acid monohydrate was added. The mixturewas heated and refluxed overnight. After completion of the reaction,methanol was distilled off under reduced pressure. The residue wasneutralized with saturated aqueous sodium bicarbonate and then extractedwith ethyl acetate. After washing with saturated brine twice, theorganic layer was separated and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give 24.5 g of white crystalline methyl3-hydroxy-4-methoxybenzoate.

¹H-NMR (CDCl₃) δ: 7.63-7.58 (2H, m), 6.67 (1H, d, J=8.1 Hz), 5.63 (1H,s), 3.98 (3H, s), 3.90 (3H, s)

Reference Example 2

A 20 g quantity of methyl 3-hydroxy-4-methoxybenzoate obtained inReference Example 1 was dissolved in 200 ml of methanol, and 24.6 ml of1,8-diazabicyclo[5,4,0]undec-7-ene and 21 g of benzyl bromide wereadded. The mixture was heated and refluxed overnight. After the reactionmixture was concentrated, water was added to the residue and extractionwith ethyl acetate was performed. The extract was washed with saturatedbrine twice, and the organic layer was separated and dried overmagnesium sulfate. After insolubles were removed by filtration, thefiltrate was concentrated under reduced pressure to give 25.5 g of whitecrystalline methyl 3-benzyloxy-4-methoxybenzoate.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=8.4, 1.8 Hz), 7.61 (1H, d, J=1.8 Hz),7.48-7.28 (5H, m), 6.91 (1H, d, J=8.4 Hz), 5.17 (2H, s), 3.93 (3H, s),3.87 (3H, s)

Reference Example 3

A 25 g quantity of the methyl 3-benzyloxy-4-methoxybenzoate obtained inReference Example 2 was dissolved in 100 ml of acetonitrile, and asolution of 11 g of sodium hydroxide in 100 ml of water was added. Themixture was stirred with heating at 40° C. for 5 hours. The reactionmixture was cooled with ice, and concentrated hydrochloric acid wasadded to give a pH of about 3. The precipitated crystals were collectedby filtration and dried under reduced pressure to give 22.1 g of whitecrystalline 3-benzyloxy-4-methoxybenzoic acid.

¹H-NMR (CDCl₃) δ: 7.77 (1H, dd, J=8.4, 1.8 Hz), 7.65 (1H, d, J=1.8 Hz),7.48-7.29 (5H, m), 6.94 (1H, d, J=8.4 Hz), 5.19 (2H, s), 3.95 (3H, s)

Reference Example 4

A 20 g quantity of the 3-benzyloxy-4-methoxybenzoic acid obtained inReference Example 3 was suspended in 200 ml of dichloromethane, and onedrop of dimethylformamide was added. A 8.1 ml quantity of oxalylchloride was added dropwise with ice-cooling and stirring. After 2hours, the reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in 50 ml of tetrahydrofuran and the resultingsolution was added dropwise to 28% aqueous ammonia with ice-cooling andstirring. The obtained mixture was stirred for 1 hour and theprecipitated crystals were collected by filtration and dried underreduced pressure to give 19.9 g of white powdery3-benzyloxy-4-methoxybenzamide.

¹H-NMR (CDCl₃) δ: 7.85-7.28 (7H, m), 6.90 (1H, d, J=8.1 Hz), 5.67 (2H,br s), 5.18 (2H, s), 3.93 (3H, s)

Reference Example 5

A 15 g quantity of 3-benzyloxy-4-methoxybenzamide obtained in ReferenceExample 4 was suspended in 450 ml of isopropanol, and 13.9 g of1,3-dichloro-2-propanone was added. The mixture was heated and refluxedovernight. After the reaction mixture was concentrated to half itsoriginal volume under reduced pressure, 200 ml of n-hexane was added tothe concentrate and the mixture was stirred. The precipitated crystalswere collected by filtration and dried under reduced pressure to give12.2 g of white powdery 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole.

¹H-NMR (CDCl₃) δ: 7.73-7.71 (3H, m), 7.50-7.29 (5H, m), 6.95 (1H, d,J=5.7 Hz), 5.20 (2H, s), 4.56 (2H, s), 3.93 (3H, s)

Reference Example 6

A 11 g quantity of 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained in Reference Example 5 was suspended in 220 ml ofethanol, and 7.5 g of sodium iodide and 9.3 g of potassium phthalimidewere added. The mixture was heated and refluxed overnight. The reactionmixture was cooled with ice, and the precipitated crystals werecollected by filtration. The obtained crude crystals were suspended andwashed with 100 ml of water. The resulting crystals were dried underreduced pressure to give 9.4 g of white powdery2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione.

¹H-NMR (CDCl₃) δ: 7.91-7.85 (2H, m) 7.76-7.69 (2H, m), 7.61-7.58 (3H, m)7.46 (2H, d, J=6.6 Hz), 7.39-7.26 (3H, m), 6.91 (1H, d, J=9 Hz), 5.18(2H, s), 4.85 (2H, s), 3.90 (3H, s)

Reference Example 7

A 9 g quantity of the2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dioneobtained in Reference Example 6 was suspended in 200 ml of ethanol, and3.1 ml of hydrazine monohydrate was added. The mixture was heated andrefluxed for 3 hours. After cooing the reaction mixture, 200 ml ofdichloromethane was added and the mixture was stirred. Insolubles wereremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(NH silica, product of Fuji Sylisia Chemical Ltd.,dichloromethane:methanol=20:1) to give 4.5 g of pale yellow powdery[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine.

¹H-NMR (CDCl₃) δ: 7.63-7.59 (2H, m) 7.53-7.46 (3H, m), 7.41-7.27 (3H, m)6.94 (1H, d, J=9 Hz), 5.20 (2H, s), 3.89 (3H, s), 3.87 (2H, s), 2.14(2H, br s)

Reference Example 8

A 15 g quantity of methyl 3-hydroxy-4-methoxybenzoate obtained inReference Example 1 was dissolved in 150 ml of dimethylformamide, and 34g of potassium carbonate and 22.2 g of (bromomethyl)cyclopropane wereadded. The mixture was heated at 90° C. overnight. Ice water was addedto the reaction mixture, and the precipitated crystals were collected byfiltration and washed with an excess of water. The obtained crystalswere dried under reduced pressure at room temperature to give 18.3 g ofwhite crystalline methyl 3-cyclopropylmethoxy-4-methoxybenzoate.

¹H-NMR (CDCl₃) δ: 7.67 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H, d, J=2.1 Hz),6.89 (1H, d, J=8.4 Hz), 3.94-3.86 (8H, m), 1.43-1.29 (1H, m), 0.70-0.58(2H, m), 0.45-0.30 (2H, m)

Reference Example 9

Using 18 g of methyl 3-cyclopropylmethoxy-4-methoxybenzoate obtained inReference Example 8 and following the procedure of Reference Example 3,16.6 g of white crystalline 3-cyclopropylmethoxy-4-methoxybenzoic acidwas obtained.

¹H-NMR (CDCl₃) δ: 7.76 (1H, dd, J=8.4, 1.8 Hz), 7.58 (1H, d, J=2.1 Hz),6.92 (1H, d, J=8.4 Hz), 3.98-3.92 (8H, m), 1.43-1.29 (1H, m), 0.70-0.58(2H, m), 0.46-0.35 (2H, m)

Reference Example 10

Using 16.5 g of 3-cyclopropylmethoxy-4-methoxybenzoic acid obtained inReference Example 9 and following the procedure of Reference Example 4,16.2 g of pale yellow powdery 3-cyclopropylmethoxy-4-methoxybenzamidewas obtained.

¹H-NMR (CDCl₃) δ: 7.43 (1H, d, J=2.1 Hz), 7.31 (1H, dd, J=8.4, 2.1 Hz),6.88 (1H, d, J=8.1 Hz), 5.75 (2H, br s), 3.97-3.89 (5H, m), 1.40-1.28(1H, m), 0.69-0.62 (2H, m), 0.39-0.33 (2H, m)

Reference Example 11

Using 13 g of 3-cyclopropylmethoxy-4-methoxybenzamide obtained inReference Example 10 and following the procedure of Reference Example 5,10.5 g of pale yellow powdery4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole wasobtained.

¹H-NMR (CDCl₃) δ: 7.65 (1H, d, J=0.9 Hz), 7.20 (1H, dd, J=8.7, 2.1 Hz),7.53 (1H, d, J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz), 4.57 (2H, s), 3.97-3.90(5H, m), 1.43-1.32 (1H, m), 0.71-0.63 (2H, m), 0.41-0.35 (2H, m)

Reference Example 12

Using 8 g of4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole obtainedin Reference Example 11 and following the procedure of Reference Example6, 10 g of white crystalline2-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dionewas obtained.

¹H-NMR (CDCl₃) δ: 7.90-7.84 (2H, m), 7.76-7.69 (2H, m), 7.62 (1H, s),7.57 (1H, dd, J=8.4, 2.1 Hz), 7.48 (1H, d, J=2.1 Hz), 6.89 (1H, d, J=8.4Hz), 4.85 (2H, s), 3.95-3.90 (5H, m), 1.41-1.31 (1H, m), 0.69-0.62 (2H,m), 0.41-0.35 (2H, m)

Reference Example 13

Using 9.5 g of2-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dioneobtained in Reference Example 12 and following the procedure ofReference Example 7, 5.1 g of white powdery[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine wasobtained.

¹H-NMR (CDCl₃) δ: 7.61-7.55 (1H, m), 7.53-7.50 (2H, m), 6.92 (1H, d,J=8.4 Hz), 3.96-3.87 (5H, m), 3.83 (2H, s), 1.41-1.33 (1H, m), 0.70-0.63(2H, m), 0.41-0.35 (2H, m)

Reference Example 14

A 5 g quantity of methyl 3-hydroxy-4-methoxybenzoate obtained inReference Example 1 was dissolved in 100 ml of dimethylformamide, and11.3 g of potassium carbonate and 5.64 g of isobutyl bromide were added.The mixture was heated at 80° C. for 6 hours. Ice water was added to thereaction mixture, and the precipitated crystals were collected byfiltration and washed with an excess of water. The resulting crystalswere dried under reduced pressure at room temperature to give 5.85 g ofwhite powdery methyl 3-isobutoxy-4-methoxybenzoate.

¹H-NMR (CDCl₃) δ: 7.65 (1H, dd, J=8.4, 2.1 Hz), 7.53 (1H, d, J=1.8 Hz),6.88 (1H, d, J=8.1 Hz), 3.96 (3H, s), 3.91 (3H, s), 3.82 (2H, d, J=6.9Hz), 2.20-2.11 (1H, m), 1.05 (6H, d, J=6.6 Hz)

Reference Example 15

Using 5.85 g of methyl 3-isobutoxy-4-methoxybenzoate obtained inReference Example 14 and following the procedure of Reference Example 3,5.6 g of white powdery 3-isobutoxy-4-methoxybenzoic acid was obtained.

¹H-NMR (CDCl₃) δ: 7.75 (1H, dd, J=8.4, 1.8 Hz), 7.58 (1H, d, J=2.1 Hz),6.91 (1H, d, J=8.7 Hz), 3.94 (3H, s), 3.83 (2H, d, J=6.6 Hz), 2.26-2.12(1H, m), 1.05 (6H, d, J=6.6 Hz)

Reference Example 16

Using 5.5 g of 3-isobutoxy-4-methoxybenzoic acid obtained in ReferenceExample 15 and following the procedure of Reference Example 4, 5.1 g ofpale yellow powdery 3-isobutoxy-4-methoxybenzamide was obtained.

¹H-NMR (CDCl₃) δ: 7.43 (1H, d, J=2.1 Hz), 7.31 (1H, dd, J=8.4, 2.1 Hz),6.87 (1H, d, J=8.7 Hz), 5.78 (2H, br s), 3.91 (3H, s), 3.83 (2H, d,J=6.6 Hz), 2.25-2.11 (1H, m), 1.04 (6H, d, J=6.6 Hz)

Reference Example 17

Using 5 g of 3-isobutoxy-4-methoxybenzamide obtained in ReferenceExample 16 and following the procedure of Reference Example 5, 3.4 g ofpale yellow powdery4-chloromethyl-2-(3-isobutoxy-4-methoxyphenyl)oxazole was obtained.

¹H-NMR (CDCl₃) δ: 7.65 (1H, s), 7.60 (1H, dd, J=8.4, 2.1 Hz), 7.53 (1H,d, J=2.1 Hz), 6.92 (1H, d, J=8.4 Hz), 4.57 (2H, s), 3.91 (3H, s), 3.85(2H, d, J=6.9 Hz), 2.27-2.13 (1H, m), 1.05 (6H, d, J=6.6 Hz)

Reference Example 18

Using 3.3 g of 4-chloromethyl-2-(3-isobutoxy-4-methoxyphenyl)oxazoleobtained in Reference Example 17 and following the procedure ofReference Example 6, 4.4 g of white powdery2-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dionewas obtained.

¹H-NMR (CDCl₃) δ: 7.91-7.84 (2H, m), 7.76-7.71 (2H, m), 7.62 (1H, s),7.55 (1H, dd, J=8.4, 2.1 Hz), 7.49 (1H, d, J=2.1 Hz), 6.88 (1H, d, J=8.4Hz), 4.85 (2H, s), 3.89 (3H, s), 3.83 (2H, d, J=6.6 Hz), 2.23-2.13 (1H,m), 1.05 (6H, d, J=6.6 Hz)

Reference Example 19

Using 4.4 g of2-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dioneobtained in Reference Example 18 and following the procedure ofReference Example 7, 2 g of white solid[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]methylamine was obtained.

¹H-NMR (CDCl₃) δ: 7.60-7.51 (3H, m), 6.92 (1H, d, J=8.4 Hz), 3.91 (3H,s), 3.87-3.84 (4H, m), 2.27-2.13 (1H, m), 1.71 (2H, br s), 1.06 (6H, d,J=6.6 Hz)

Reference Example 20

Using 10 g of methyl 3-hydroxy-4-methoxybenzoate obtained in ReferenceExample 1 and following the procedure of Reference Example 14, 12.5 g ofwhite powdery methyl 4-methoxy-3-(2,2,2-trifluoroethoxy)benzoate wasobtained.

¹H-NMR (CDCl₃) δ: 7.79 (1H, dd, J=8.7, 1.8 Hz), 7.63 (1H, s), 6.94 (1H,d, J=8.7 Hz), 4.42 (2H, q, J=8.1 Hz), 3.94 (3H, s), 3.91 (3H, s)

Reference Example 21

Using 12 g of methyl 4-methoxy-3-(2,2,2-trifluoro ethoxy)benzoateobtained in Reference Example 20 and following the procedure ofReference Example 3, 11.5 g of white powdery4-methoxy-3-(2,2,2-trifluoroethoxy)benzoic acid was obtained.

¹H-NMR (CDCl₃) δ: 7.86 (1H, dd, J=8.4, 1.8 Hz), 7.67 (1H, d, J=1.8 Hz),6.97 (1H, d, J=8.4 Hz), 4.43 (2H, q, J=8.4 Hz), 3.96 (3H, s)

Reference Example 22

Using 11.5 g of 4-methoxy-3-(2,2,2-trifluoroethoxy)benzoic acid obtainedin Reference Example 21 and following the procedure of Reference Example4, 10.8 g of white powdery 4-methoxy-3-(2,2,2-trifluoroethoxy)benzamidewas obtained.

¹H-NMR (CDCl₃) δ: 7.50 (1H, br s), 7.49 (1H, dd, J=8.4, 2.4 Hz), 6.94(1H, d, J=8.4 Hz), 4.43 (2H, q, J=8.4 Hz), 3.93 (3H, s)

Reference Example 23

Using 10.5 g of 4-methoxy-3-(2,2,2-trifluoroethoxy)benzamide obtained inReference Example 22 and following the procedure of Reference Example 5,7.1 g of pale yellow powdery4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole wasobtained.

¹H-NMR (CDCl₃) δ: 7.75 (1H, dd, J=8.4, 2.1 Hz), 7.66 (1H, br s), 7.64(1H, d, J=2.1 Hz), 6.98 (1H, d, J=8.4 Hz), 4.56 (2H, s), 4.45 (2H, q,J=8.4 Hz), 3.94 (3H, s)

Reference Example 24

Using 3 g of4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazoleobtained in Reference Example 23 and following the procedure ofReference Example 6, 3.6 g of white powdery2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}isoindolin-1,3-dionewas obtained.

¹H-NMR (CDCl₃) δ: 7.91-7.85 (2H, m), 7.76-7.64 (3H, m), 7.60 (1H, s),7.59 (1H, d, J=2.1 Hz), 6.94 (1H, d, J=8.7 Hz), 4.85 (2H, s), 4.43 (2H,q, J=8.4 Hz), 3.91 (3H, s)

Reference Example 25

Using 3.6 g of 2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}isoindolin-1,3-dione obtained inReference Example 24 and following the procedure of Reference Example 7,1.93 g of white powdery{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylaminewas obtained.

¹H-NMR (CDCl₃) δ: 7.73 (1H, dd, J=8.4, 2.1 Hz), 7.63 (1H, d, J=2.1 Hz),7.52 (1H, s), 6.98 (1H, d, J=8.4 Hz), 4.46 (2H, q, J=8.4 Hz), 3.93 (3H,s), 3.83 (2H, s), 1.55 (2H, br s)

Reference Example 26

Using 9.5 g of ethyl vanillate and following the procedure of ReferenceExample 14, 11 g of white powdery ethyl3-methoxy-4-(2,2,2-trifluoroethoxy)benzoate was obtained.

¹H-NMR (CDCl₃) δ: 7.65 (1H, dd, J=8.4, 2.1 Hz), 7.60 (1H, d, J=2.1 Hz),6.96 (1H, d, J=8.4 Hz), 4.49-4.33 (4H, m), 3.93 (3H, s), 1.39 (3H, t,J=6.9 Hz)

Reference Example 27

A 12 g quantity of ethyl 3-methoxy-4-(2,2,2-trifluoroethoxy)benzoateobtained in Reference Example 26 was suspended in 120 ml of 47%hydrobromic acid, and the suspension was heated and refluxed overnight.The reaction mixture was poured into ice water, and the precipitatedcrystals were collected by filtration, washed with an excess of water,and then dried under reduced pressure to give 8.4 g of pale red powdery3-hydroxy-4-(2,2,2-trifluoroethoxy)benzoic acid.

¹H-NMR (CDCl₃) δ: 7.71-7.66 (2H, m), 6.91 (1H, d, J=5.1 Hz), 5.55 (1H,br s), 4.50 (2H, q, J=7.8 Hz)

Reference Example 28

An 8.4 g quantity of 3-hydroxy-4-(2,2,2-trifluoro ethoxy)benzoic acidobtained in Reference Example 27 was suspended in 150 ml of ethanol, and0.5 ml of concentrated sulfuric acid was added. The mixture was heatedand refluxed overnight. After completion of the reaction, ethanol wasdistilled off under reduced pressure. The residue was neutralized withsaturated aqueous sodium bicarbonate and then extracted with ethylacetate. After washing with saturated brine twice, the organic layer wasseparated and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give 7.2 g of white crystalline ethyl3-hydroxy-4-(2,2,2-trifluoroethoxy)benzoate.

¹H-NMR (CDCl₃) δ: 7.66-7.60 (2H, m), 6.87 (1H, d, J=8.1 Hz), 5.54 (1H,s), 4.48 (2H, q, J=7.8 Hz), 4.35 (2H, q, J=7.2 Hz), 1.38 (3H, t, J=7.2Hz)

Reference Example 29

Using 7 g of ethyl 3-hydroxy-4-(2,2,2-trifluoro ethoxy)benzoate obtainedin Reference Example 28 and following the procedure of Reference Example14, 8.5 g of white powdery ethyl3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoate was obtained.

¹H-NMR (CDCl₃) δ: 7.63 (1H, dd, J=8.7, 2.1 Hz), 7.58 (1H, d, J=2.1 Hz),7.00 (1H, d, J=8.7 Hz), 4.48 (2H, q, J=8.1 Hz), 4.35 (2H, q, J=6.9 Hz),3.92 (2H, d, J=7.2 Hz), 1.41-1.25 (4H, m), 0.69-0.60 (2H, m), 0.40-0.32(2H, m)

Reference Example 30

Using 8.5 g of ethyl3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoate obtained inReference Example 29 and following the procedure of Reference Example 3,7.5 g of white powdery3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoic acid was obtained.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=8.4, 1.8 Hz), 7.63 (1H, d, J=2.1 Hz),7.02 (1H, d, J=8.1 Hz), 4.51 (2H, q, J=8.1 Hz), 3.93 (2H, d, J=7.2 Hz),1.37-1.25 (1H, m), 0.69-0.60 (2H, m), 0.41-0.35 (2H, m)

Reference Example 31

Using 7 g of 3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzoic acidobtained in Reference Example 30 and following the procedure ofReference Example 4, 7.35 g of white solid3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzamide was obtained.

¹H-NMR (CDCl₃) δ: 7.48 (1H, d, J=2.1 Hz), 7.28-7.25 (1H, m), 7.01 (1H,d, J=8.4 Hz), 4.48 (2H, q, J=8.4 Hz), 3.93 (2H, d, J=6.9 Hz), 1.37-1.25(1H, m), 0.69-0.60 (2H, m), 0.41-0.35 (2H, m)

Reference Example 32

Using 5 g of 3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)benzamideobtained in Reference Example 31 and following the procedure ofReference Example 5, 3.1 g of white powdery4-chloromethyl-2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazolewas obtained.

¹H-NMR (CDCl₃) δ: 7.67 (1H, s), 7.59-7.56 (2H, m), 7.05 (1H, d, J=9.0Hz), 4.56 (2H, s), 4.48 (2H, q, J=8.4 Hz), 1.35-1.26 (1H, m), 0.70-0.63(2H, m), 0.41-0.35 (2H, m)

Reference Example 33

Using 0.85 g of4-chloromethyl-2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazoleobtained in Reference Example 32 and following the procedure ofReference Example 6, 0.6 g of white powdery2-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}isoindolin-1,3-dionewas obtained.

¹H-NMR (CDCl₃) δ: 7.91-7.84 (2H, m), 7.76-7.69 (2H, m), 7.64 (1H, s),7.60-7.51 (2H, m), 7.01 (1H, d, J=8.7 Hz), 4.85 (2H, s), 4.46 (2H, q,J=8.4 Hz), 3.93 (2H, d, J=6.9 Hz), 1.35-1.24 (1H, m), 0.68-0.61 (2H, m),0.40-0.34 (2H, m)

Reference Example 34

Using 0.55 g of2-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}isoindolin-1,3-dioneobtained in Reference Example 33 and following the procedure ofReference Example 7, 0.32 g of white powdery {2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamine wasobtained.

¹H-NMR (CDCl₃) δ: 7.61-7.52 (3H, m), 7.05 (1H, d, J=8.7 Hz), 4.48 (2H,q, J=8.4 Hz), 3.95 (2H, d, J=7.2 Hz), 3.84 (2H, s), 1.56 (2H, br s),1.35-1.24 (1H, m), 0.70-0.61 (2H, m), 0.41-0.35 (2H, m)

Reference Example 35

Using 20 g of 3,4-diethoxybenzamide and following the procedure ofReference Example 5, 24.5 g of white powdery4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole was obtained.

¹H-NMR (CDCl₃) δ: 7.65 (1H, s), 7.58 (1H, dd, J=8.4, 1.8 Hz), 7.54 (1H,d, J=1.8 Hz), 6.92 (1H, d, J=8.4 Hz), 4.56 (2H, s), 4.18 (2H, q, J=6.9Hz), 4.15 (2H, q, J=6.9 Hz), 1.48 (6H, t, J=6.9 Hz)

Reference Example 36

Using 8 g of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole obtained inReference Example 35 and following the procedure of Reference Example 6,10 g of white powdery2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione wasobtained.

¹H-NMR (CDCl₃) δ: 7.88 (2H, m), 7.72 (2H, m), 7.62 (1H, s), 7.54 (1H, d,J=8.4, 2.1 Hz), 7.50 (1H, d, J=2.1 Hz), 6.88 (1H, d, J=8.4 Hz), 4.85(2H, s), 4.16 (2H, q, J=6.9 Hz), 4.11 (2H, q, J=6.9 Hz), 1.47 (6H, t,J=6.9 Hz)

Reference Example 37

Using 10 g of2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione obtainedin Reference Example 36 and following the procedure of Reference Example7, 5.7 g of white powdery [2-(3,4-diethoxyphenyl)oxazol-4-yl]methylaminewas obtained.

¹H-NMR (CDCl₃) δ: 7.56 (1H, d, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz),7.51 (1H, s), 6.91 (1H, d, J=8.4 Hz), 4.18 (2H, q, J=6.9 Hz), 4.14 (2H,q, J=6.9 Hz), 1.80 (1H, br s), 3.84 (2H, s), 1.48 (3H, t, J=6.9 Hz),1.48 (3H, t, J=6.9 Hz)

Reference Example 38

Using 2.0 g of 3,4-dimethoxybenzamide and following the procedure ofReference Example 5, 2.4 g of white powdery4-chloromethyl-2-(3,4-dimethoxyphenyl)oxazole was obtained.

¹H-NMR (CDCl₃) δ: 7.66 (1H, s), 7.62 (1H, dd, J=8.4, 1.8 Hz), 7.55 (1H,d, J=1.8 Hz), 6.93 (1H, d, J=8.4 Hz), 4.52 (2H, s), 3.95 (3H, s), 3.91(3H, s)

Reference Example 39

Using 2.4 g of 4-chloromethyl-2-(3,4-dimethoxyphenyl)oxazole obtained inReference Example 38 and following the procedure of Reference Example 6,2.3 g of white powdery2-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione wasobtained.

Reference Example 40

Using 2.3 g of the2-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dioneobtained in Reference Example 39 and following the procedure ofReference Example 7, 1.3 g of white powdery[2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine was obtained. ¹H-NMR(CDCl₃) δ: 7.60 (1H, d, J=8.1, 2.1 Hz), 7.54 (1H, d, J=2.1 Hz), 6.92(1H, d, J=8.1 Hz), 3.96 (3H, s), 3.93 (3H, s), 3.85 (2H, s), 1.81 (2H,br s)

Reference Example 41

A 9 g quantity of 4-difluoromethoxy-3-hydroxy benzaldehyde was dissolvedin 180 ml of acetonitrile, and 13.1 g of potassium carbonate and 8.6 mlof benzyl bromide were added. The mixture was stirred at roomtemperature for 4 hours. After insolubles were removed by filtration,the filtrate was concentrated and the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=1:1) to give 11.9 g ofcolorless oily 3-benzyloxy-4-difluoromethoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 10.21 (1H, s), 7.56 (1H, t, J=74.1 Hz), 7.53-7.28 (7H,m), 6.68 (1H, d, J=8.4 Hz), 5.20 (2H, s)

Reference Example 42

A 6 g quantity of 3-benzyloxy-4-difluoromethoxybenzaldehyde obtained inReference Example 41 was dissolved in 500 ml of acetone, and 17 g ofpotassium permanganate was added. The mixture was heated and refluxedovernight. After distilling off acetone from the reaction mixture, 100ml of 5N sodium hydroxide was added to the residue, and insolubles wereremoved by filtration. Concentrated hydrochloric acid was added to thefiltrate to give a pH of about 3, and the precipitated crystals werecollected by filtration. The obtained crystals were dried under reducedpressure to give 2.1 g of brownish powdery3-benzyloxy-4-difluoromethoxybenzoic acid.

¹H-NMR (CDCl₃) δ: 7.78-7.72 (2H, m), 7.73-7.32 (5H, m), 7.33-7.24 (1H,m), 6.67 (1H, t, J=74.1 Hz), 5.20 (2H, s)

Reference Example 43

A 2 g quantity of 3-benzyloxy-4-difluoromethoxybenzoic acid obtained inReference Example 42 was suspended in 40 ml of dichloromethane, and onedrop of dimethylformamide was added. A 0.7 ml quantity of oxalylchloride was added dropwise with ice-cooling and stirring. After 2hours, the reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in 5 ml of acetone and the resulting solution wasadded dropwise to 28% aqueous ammonia with ice-cooling and stirring. Theobtained mixture was stirred for 1 hour and the precipitated crystalswere collected by filtration and dried under reduced pressure to give1.9 g of white powdery 3-benzyloxy-4-difluoromethoxybenzamide.

¹H-NMR (CDCl₃) δ: 7.62 (1H, d, J=1.8 Hz), 7.45-7.20 (7H, m), 6.63 (1H,t, J=74.4 Hz), 5.19 (2H, s), 4.73 (2H, br s)

Reference Example 44

A 1.8 g quantity of 3-benzyloxy-4-difluoromethoxybenzamide obtained inReference Example 43 was suspended in 50 ml of isopropanol, and 1.17 gof 1,3-dichloro-2-propanone was added. The mixture was heated andrefluxed overnight. The reaction mixture was concentrated, and theresulting residue was purified by silica gel column chromatography(dichloromethane). The obtained crude crystals were recrystallized fromisopropanol to give 0.7 g of white powdery2-(3-benzyloxy-4-difluoromethoxyphenyl)-4-chloromethyloxazole.

¹H-NMR (CDCl₃) δ: 7.44 (1H, d, J=1.8 Hz), 7.70 (1H, s), 7.48-7.32 (5H,m), 7.28-7.24 (1H, m), 6.63 (1H, t, J=74.7 Hz), 5.21 (2H, s), 4.57 (2H,s)

Reference Example 45

A 0.37 g quantity of2-(3-benzyloxy-4-difluoromethoxyphenyl)-4-chloromethyloxazole obtainedin Reference Example 44 was dissolved in 20 ml of ethanol, and 0.23 g ofsodium iodide and 0.27 g of potassium phthalimide were added. Themixture was heated and refluxed for 4 hours. After the reaction mixturewas concentrated, water was added to the residue and extraction withethyl acetate was performed. The organic layer was washed with watertwice and concentrated by removing the solvent and the residue waspurified by silica gel column chromatography(dichloromethane:methanol=20:1) to give 0.3 g of white powdery2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione.

¹H-NMR (CDCl₃) δ: 7.90-7.84 (2H, m), 7.76-7.71 (4H, m), 7.59 (1H, dd,J=8.4, 2.1 Hz), 7.47-7.30 (5H, m), 7.22 (1H, d, J=2.4 Hz), 6.60 (1H, t,J=74.7 Hz), 5.20 (2H, s), 4.87 (2H, s)

Reference Example 46

A 0.3 g quantity of2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dioneobtained in Reference Example 45 was suspended in 10 ml of ethanol, and0.1 ml of hydrazine monohydrate was added. The mixture was heated andrefluxed for 2 hours. After cooling the reaction mixture, theprecipitated insolubles were removed by filtration. The filtrate wasconcentrated under reduced pressure to give 0.13 g of colorless oily[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]methylamine.

¹H-NMR (CDCl₃) δ: 7.74 (1H, d, J=1.8 Hz), 7.61 (1H, dd, J=7.8, 1.8 Hz),7.47 (1H, d, J=1.8 Hz), 7.45-7.31 (5H, m), 7.26-7.20 (1H, m), 6.62 (1H,t, J=74.7 Hz), 5.21 (2H, s), 3.85 (2H, br s).

Reference Example 47

A 5.25 g quantity of sodium hydride was suspended in 150 ml oftetrahydrofuran, and a solution of 14.4 g of dimethyl malonate in 75 mlof tetrahydrofuran was added dropwise with ice-cooling over 15 minutes.After stirring for 30 minutes, a solution of 25 g of the2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained inReference Example 5 in 150 ml of dimethylformamide was added dropwiseover 15 minutes. After the dropwise addition, the mixture was stirred at50 to 60° C. for 4 hours, and an aqueous saturated ammonium chloridesolution was added with ice-cooling. After stirring the mixture for 30minutes, water was added and extraction with ethyl acetate wasperformed. The extract was dried over anhydrous magnesium sulfate, andthe solvent was distilled off. The residue was recrystallized from amixture of ethyl acetate and diisopropyl ether to give 26.5 g of whitepowdery dimethyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]malonate.

¹H-NMR (DMSO-d₆) δ: 7.89 (1H, s), 7.59-7.31 (7H, m), 7.15 (1H, d, J=7.8Hz), 5.16 (2H, s), 3.90-3.84 (4H, m), 3.71 (6H, s), 3.04 (2H, d, J=7.8Hz)

Reference Example 48

A 26.52 g quantity of the dimethyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]malonate obtained inReference Example 47 was suspended in 53 ml of dimethyl sulfoxide, and2.62 g of lithium chloride and 1.12 ml of purified water were added. Themixture was stirred at 130° C. for 4 hours. After the reaction mixturewas allowed to cool, water was added and extraction with ethyl acetatewas performed. The extract was dried over anhydrous magnesium sulfate,and the solvent was distilled off. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=3:1) to give 16 g ofwhite powdery methyl3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate.

¹H-NMR (CDCl₃) δ: 7.62-7.59 (2H, m), 7.47 (2H, d, J=6.9 Hz), 7.40-7.31(4H, m), 6.93 (1H, d, J=8.4 Hz), 5.20 (2H, s), 3.92 (3H, s), 3.69 (3H,s), 2.91 (2H, t, J=7.2 Hz), 2.72 (2H, t, J=7.2 Hz)

Reference Example 49

A 0.48 g quantity of sodium hydride was suspended in 15 ml oftetrahydrofuran, and a solution of 1.31 g of dimethyl malonate in 7.5 mlof tetrahydrofuran was added dropwise over 15 minutes. After the mixturewas stirred for 30 minutes, a solution of 3.0 g of4-chloromethyl-2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazoleobtained in Reference Example 32 dissolved in 15 ml of dimethylformamidewas added over 15 minutes. After the dropwise addition, the mixture washeated at 50 to 60° C. with stirring for 4 hours. An aqueous saturatedammonium chloride solution was added to the reaction mixture withice-cooling and stirred was continued for 30 minutes. Water was addedand extraction with ethyl acetate was performed. The extract was driedover anhydrous magnesium sulfate, and the solvent was distilled off. A8.0 ml quantity of dimethylsulfoxide, 0.35 g of lithium chloride, and0.15 ml of purified water were added to the residue, and the mixture washeated with stirring at 130° C. for 4 hours. After the reaction mixturewas allowed to cool, water was added and extraction with ethyl acetatewas performed. The extract was dried over anhydrous magnesium sulfateand the solvent was distilled off. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=4:1) to give 1.63 g ofcolorless oily methyl3-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propionate.

¹H-NMR (CDCl₃) δ: 7.56-7.53 (2H, m), 7.43 (1H, s), 7.04 (1H, d, J=8.4Hz), 4.47 (2H, q, J=8.4 Hz), 3.94 (2H, d, J=6.6 Hz), 3.69 (3H, s), 2.91(2H, t, J=7.2 Hz), 2.72 (2H, t, J=7.2 Hz), 0.88 (1H, t, J=6.6 Hz),0.69-0.65 (2H, m), 0.40-0.35 (2H, m)

Reference Example 50

A 0.5 g quantity of 2-cyclopropylethanol and 3.1 ml of triethylaminewere dissolved in 10 ml of ethyl acetate, and 0.75 ml of methanesulfonylchloride was added with ice-cooling and stirring. After stirring for 30minutes, water was added to the reaction mixture and extraction wasperformed. The organic layer was washed with water twice andconcentrated by removing the solvent under reduced pressure to give 1 gof pale yellow oily 2-cyclopropylethyl methanesulfonate.

¹H-NMR (CDCl₃) δ: 4.29 (2H, t, J=6.6 Hz), 3.03 (3H, s), 1.66 (2H, q,J=6.6 Hz), 0.84-0.70 (1H, m), 0.54-0.47 (2H, m), 0.20-0.10 (2H, m)

Reference Example 51

Using 2 g of 2-cyclopentylethanol and following the procedure ofReference Example 50, 3.4 g of pale yellow oily 2-cyclopentylethylmethanesulfonate was obtained.

¹H-NMR (CDCl₃) δ: 4.24 (2H, t, J=6.6 Hz), 3.03 (3H, s), 1.95-1.73 (5H,m), 1.70-1.48 (4H, m), 1.29-1.06 (2H, m)

Reference Example 52

Using 0.5 g of cyclopentylmethanol and following the procedure ofReference Example 50, 0.7 g of pale yellow oily cyclopentylmethylmethanesulfonate was obtained.

¹H-NMR (CDCl₃) δ: 4.11 (2H, d, J=6.9 Hz), 3.04 (3H, s), 2.38-2.23 (1H,m), 1.86-1.76 (2H, m), 1.74-1.53 (4H, m), 1.36-1.24 (2H, m)

Reference Example 53

A 25 g quantity of 1-(2-hydroxyphenyl)ethanone and 76 g of potassiumcarbonate were suspended in 500 ml of acetonitrile, and 31 ml of allylbromide was added. The mixture was stirred at room temperature for 48hours. The reaction mixture was filtered to remove insolubles, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to give 34 g of pale yellow oily1-(2-allyloxyphenyl)ethanone.

¹H-NMR (CDCl₃) δ: 7.73 (1H, dd, J=7.8, 1.8 Hz), 7.46-7.40 (1H, m),7.02-6.93 (2H, m), 6.15-6.02 (1H, m), 5.47-5.30 (2H, m), 4.66-4.61 (2H,m), 2.64 (3H, s)

Reference Example 54

A 40 g quantity of 3,4-diethoxybenzamide and 80 g of methyl5-bromo-4-oxopentanoate (containing about 35% of methyl3-bromo-4-oxopentanoate) were added to 400 ml of dimethylformamide, andthe mixture was stirred at 130° C. for 16 hours. The reaction mixturewas concentrated under reduced pressure and diluted with ethyl acetate.Ethyl acetate (500 ml) and saturated sodium bicarbonate solution (500ml) were gradually added with stirring, and stirring was continued. Theorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:8 to 1:4) to give 18g of white powdery methyl3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate.

¹H-NMR (CDCl₃) δ: 7.65-7.55 (2H, m), 7.51 (1H, s), 6.93 (1H, d, J=8.1Hz), 4.19 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 3.80 (3H, s),3.00-2.90 (2H, m), 2.70-2.60 (2H, m), 1.50 (3H, t, J=6.9 Hz), 1.49 (3H,t, J=6.9 Hz)

Reference Example 55

A 37.9 g quantity of 3,4-dibenzyloxybenzamide and 28.8 g of1,3-dichloro-2-propanone were suspended in 500 ml of propanol, and thesuspension was heated and refluxed for 3 days. After cooling, thereaction mixture was concentrated to half its original volume underreduced pressure and 300 ml of diisopropyl ether was added. Theprecipitated crystals were collected by filtration and recrystallizedfrom acetone-methanol-diisopropyl ether. The obtained crystals weredried under reduced pressure to give 20.1 g of colorless powdery2-(3,4-bis(benzyloxy)phenyl)-4-chloromethyloxazole.

¹H-NMR (CDCl₃) δ: 7.66 (1H, d, J=2.1 Hz), 7.64 (1H, s), 7.59 (1H, dd,J=8.4, 2.1 Hz), 7.50-7.28 (10H, m), 6.99 (1H, d, J=8.4 Hz), 5.22 (2H,s), 5.21 (2H, s), 4.55 (2H, s)

Reference Example 56

Using 10 g of 2-(3,4-bis(benzyloxy)phenyl)-4-chloromethyloxazoleobtained in Reference Example 55 and following the procedure ofReference Example 47, 12.3 g of colorless oily dimethyl2-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-ylmethyl]malonate was obtained.

¹H-NMR (CDCl₃) δ: 7.61 (1H, d, J=2.1 Hz), 7.58-7.27 (12H, m), 6.97 (1H,d, J=8.4 Hz), 5.23-5.20 (4H, m), 3.89 (1H, t, J=7.5 Hz), 3.75 (3H, s),3.73 (3H, s), 3.18 (2H, d, J=7.5 Hz)

Reference Example 57

Using 12.3 g of dimethyl2-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-ylmethyl]malonate obtained inReference Example 56 and following the procedure of Reference Example48, 4 g of pale red powdery methyl3-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-yl]propionate was obtained.

¹H-NMR (CDCl₃) δ: 7.63 (1H, d, J=2.1 Hz), 7.57-7.27 (12H, m), 6.97 (1H,d, J=8.4 Hz), 5.21 (2H, d, J=7.2 Hz), 3.69 (3H, s), 2.90 (2H, t, J=7.2Hz), 2.72 (2H, d, J=7.2 Hz)

Reference Example 58

Using 29.4 g of 3-ethoxy-4-methoxybenzamide and 57 g of1,3-dichloro-2-propanone and following the procedure of ReferenceExample 55, 19.9 g of white powdery4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazole was obtained.

¹H-NMR (CDCl₃) δ: 7.65 (1H, s), 7.61 (1H, dd, J=8.1, 2.1 Hz), 7.55 (1H,d, J=2.1 Hz), 6.92 (1H, d, J=8.1 Hz), 4.56 (2H, s), 4.18 (2H, q, J=6.9Hz), 3.93 (3H, s), 1.50 (3H, t, J=6.9 Hz)

Reference Example 59

A 25 g quantity of ethyl 3,4-dihydroxybenzoate was dissolved in 250 mlof dimethylformamide, and 5.5 g of sodium hydride was added withice-cooling and stirring. The mixture was stirred, and a solution of16.3 ml of benzylbromide in 10 ml of dimethylformamide was addeddropwise. After the dropwise addition, the mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture andextraction with ethyl acetate was performed. The organic layer waswashed with water twice and concentrated by removing the solvent underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1) to give 15 g of crudecrystals. The crude crystals were recrystallized from a mixture of 30 mlof n-hexane and 15 ml of ethyl acetate to give 8.6 g of colorless platecrystalline ethyl 4-benzyloxy-3-hydroxybenzonate.

¹H-NMR (CDCl₃) δ: 7.67-7.47 (2H, m), 7.41-7.30 (5H, m), 6.94 (1H, d,J=8.7 Hz), 5.67 (1H, s), 5.16 (2H, s), 4.34 (2H, q, J=7.2 Hz), 1.37 (3H,t, J=7.2 Hz)

Reference Example 60

Using ethyl 4-benzyloxy-3-hydroxybenzonate obtained in Reference Example59 and following the procedure of Reference Example 2, ethyl4-benzyloxy-3-ethoxybenzoate was obtained.

¹H-NMR (CDCl₃) δ: 7.61-7.55 (2H, m), 7.45-7.27 (5H, m), 6.90 (1H, d,J=8.1 Hz), 5.21 (2H, s), 4.34 (2H, q, J=6.9 Hz), 4.17 (2H, q, J=6.9 Hz),1.48 (3H, t, J=6.9 Hz), 1.37 (3H, t, J=6.9 Hz)

Reference Example 61

Using ethyl 4-benzyloxy-3-ethoxybenzoate obtained in Reference Example60 and following the procedure of Reference Example3,4-benzyloxy-3-ethoxybenzoic acid was obtained.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=8.4, 1.2 Hz), 7.61 (1H, d, J=1.2 Hz),7.45-7.28 (5H, m), 6.92 (1H, d, J=8.4 Hz), 5.23 (2H, s), 4.17 (2H, q,J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)

Reference Example 62

Using 4-benzyloxy-3-ethoxybenzoic acid obtained in Reference Example 61and following the procedure of Reference Example 4, colorless needlecrystalline 4-benzyloxy-3-ethoxybenzamide was obtained.

¹H-NMR (CDCl₃) δ: 7.47-7.21 (7H, m), 6.88 (1H, d, J=8.1 Hz), 5.21 (2H,s), 4.18 (2H, q, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Reference Example 63

Using 4-benzyloxy-3-ethoxybenzamide obtained in Reference Example 62 andfollowing the procedure of Reference Example 5, colorless powdery4-chloromethyl-2-(4-benzyloxy-3-ethoxyphenyl)oxazole was obtained.

¹H-NMR (CDCl₃) δ: 7.64 (1H, s), 7.57-7.30 (7H, m), 6.94 (1H, d, J=8.4Hz), 5.20 (2H, s), 4.56 (2H, s), 4.20 (2H, q, J=7.2 Hz), 1.49 (3H, t,J=7.2 Hz)

Reference Example 64

A 6.81 g quantity of sodium iodide and 5.09 g of sodium bicarbonate wereadded to a suspension of 10 g of2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained inReference Example 5 in 60 ml of dimethylsulfoxide. The mixture washeated at 120° C. with stirring for 30 minutes. After the reactionmixture was allowed to cool, saturated brine was added and extractionwith ethyl acetate was performed. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was then distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1) to give 2.98 g of yellow oily2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde.

¹H-NMR (CDCl₃) δ: 9.98 (1H, s), 8.26 (1H, s), 7.71 (1H, dd, J=8.1, 2.1Hz), 7.69 (1H, br s), 7.48 (2H, br d, J=8.4 Hz), 7.42-7.31 (3H, m), 6.98(1H, d, J=8.1 Hz), 5.21 (2H, s), 3.95 (3H, s)

Reference Example 65

Using4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazoleobtained in Reference Example 23 and following the procedure ofReference Example 64, colorless powdery2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole-4-carbaldehyde wasobtained.

¹H-NMR (CDCl₃) δ: 9.99 (1H, s), 8.28 (1H, s), 7.82 (1H, dd, J=8.4, 2.1Hz), 7.71 (1H, d, J=2.1 Hz), 7.01 (1H, d, J=8.4 Hz), 4.46 (2H, q, J=8.4Hz), 3.95 (3H, s)

Reference Example 66

Using 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole obtained in ReferenceExample 35 and following the procedure of Reference Example 64, paleyellow powdery 2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde wasobtained.

¹H-NMR (CDCl₃) δ: 9.99 (1H, s), 8.26 (1H, s), 7.65 (1H, dd, J=8.4, 2.1Hz), 7.62 (1H, d, J=2.1 Hz), 6.94 (1H, d, J=8.4 Hz), 4.19 (2H, q, J=7.2Hz), 4.17 (2H, q, J=7.2 Hz), 1.50 (6H, t, J=7.2 Hz)

Reference Example 67

Using 12.7 g of 3-isopropoxy-4-methoxybenzoic acid and following theprocedure of Reference Example 4, white powdery3-isopropoxy-4-methoxybenzamide was obtained.

¹H-NMR (CDCl₃) δ: 7.46 (1H, d, J=2.1 Hz), 7.34 (1H, dd, J=8.4, 2.1 Hz),6.87 (1H, d, J=8.4 Hz), 5.93 (1H, br s), 4.62 (1H, m), 3.90 (3H, s),1.38 (6H, d, J=6.0 Hz).

Reference Example 68

Using 11.4 g of 3-isopropoxy-4-methoxybenzamide obtained in ReferenceExample 67 and 25 g of 1,3-dichloro-2-propanone and following theprocedure of Reference Example 5, 12.2 g of white powdery4-chloromethyl-2-(3-isopropoxy-4-methoxyphenyl)oxazole was obtained.

¹H-NMR (CDCl₃) δ: 7.65 (1H, s), 7.61 (1H, dd, J=8.4, 2.1 Hz), 7.57 (1H,d, J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz), 4.64 (1H, m), 4.53 (2H, s), 3.90(3H, s), 1.40 (6H, d, J=6.0 Hz)

Reference Example 69

Using 4-chloromethyl-2-(3-isopropoxy-4-methoxyphenyl) oxazole obtainedin Reference Example 68 and following the procedure of Reference Example64, pale yellow powdery2-(3-isopropoxy-4-methoxyphenyl)oxazole-4-carbaldehyde was obtained.

¹H-NMR (CDCl₃) δ: 9.99 (1H, s), 8.27 (1H, s), 7.68 (1H, dd, J=8.1, 2.1Hz), 7.64 (1H, d, J=2.1 Hz), 6.95 (1H, d, J=8.1 Hz), 4.67 (1H, sept.,J=6.3 Hz), 3.92 (3H, s), 1.41 (6H, d, J=6.3 Hz)

Reference Example 70

A 10 g quantity of 1-(2-hydroxyphenyl)ethanone was dissolved in 100 mlof dimethylformamide, and 11.2 ml of chloromethyl methyl ether and 25.4g of potassium carbonate were added. The mixture was stirred at 50° C.for 6 hours and then at room temperature for 4 days. After insolubleswere removed from the reaction mixture by filtration, ice water wasadded to the filtrate and extraction with ethyl acetate was performed.The organic layer was washed with water and dried over anhydrousmagnesium sulfate. The organic layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=5:1) to give 6.26 g of colorlessoily 1-(2-methoxymethoxyphenyl)ethanone.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.43 (1H, td, J=7.8, 1.8Hz), 7.18 (1H, d, J=7.8 Hz), 7.05 (1H, t, J=7.8 Hz), 5.28 (2H, s), 3.52(3H, s), 2.64 (3H, s)

Reference Example 71

A 3 g quantity of methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionateobtained in Reference Example 54 was suspended in 5 ml of methanol, and5 ml of a 20% aqueous sodium hydroxide solution was added. The mixturewas heated and refluxed for 4 hours. After cooling the reaction mixtureto room temperature, extraction with dichloromethane was performed. Thedichloromethane layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was distilled off and the obtainedcrystals were dried to give 2.8 g of white powdery3-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]propionic acid.

¹H-NMR (CDCl₃) δ: 7.65-7.55 (3H, m), 7.51 (1H, d, J=2.1 Hz), 6.91 (1H,d, J=8.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 3.00-2.90(2H, m), 2.90-2.80 (2H, m), 1.48 (3H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9Hz)

Reference Example 72

Using 10 g of 4-benzyloxy-3-methoxybenzamide and following the procedureof Reference Example 54, 2 g of white powdery methyl3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionate was obtained.

¹H-NMR (CDCl₃) δ: 7.54-7.28 (8H, m) 6.93 (1H, d, J=8.1 Hz), 5.20 (2H,s), 3.97 (3H, s), 3.68 (3H, s), 2.91 (2H, t, J=7.5 Hz), 2.64 (2H, t,J=7.5 Hz)

Reference Example 73

Using 2 g of methyl3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionate obtained inReference Example 72 and following the procedure of Reference Example71, 1.03 g of white powdery3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionic acid wasobtained.

¹H-NMR (CDCl₃) δ: 12.20 (1H, s), 7.86 (1H, s), 7.51-7.31 (7H, m) 7.17(1H, d, J=8.4 Hz), 5.15 (2H, s), 3.85 (3H, s), 2.75 (2H, t, J=7.5 Hz),2.59 (2H, t, J=7.5 Hz)

Reference Example 74

A 0.4 g quantity of 4-chloromethyl-2-(3,4-diethoxy phenyl)oxazoleobtained in Reference Example 35 was dissolved in 15 ml of methylamine(40% methanol solution), and was heated and refluxed for 1 hour. Thereaction mixture was concentrated and the obtained residue was driedunder reduced pressure to give 0.23 g of yellow oily[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]methylamine.

¹H-NMR (CDCl₃) δ: 8.00 (1H, s), 7.58-7.50 (2H, m), 6.90 (1H, d, J=8.4Hz), 4.21-4.10 (6H, m), 2.76 (3H, s), 1.51-1.45 (6H, m)

Reference Example 75

Using ethyl 2-chloroacetoacetate and 16 g of 3,4-diethoxybenzamide andfollowing the procedure of Reference Example 5, 3.8 g of ethyl[2-(3,4-dimethoxyphenyl)oxazol-4-yl]acetate was obtained.

¹H-NMR (CDCl₃) δ: 7.64 (1H, s), 7.60-7.50 (2H, m), 6.91 (1H, d, J=8.1Hz), 4.25-4.10 (6H, m), 3.58 (2H, s), 1.50-1.40 (6H, m), 1.29 (3H, t,J=6.9 Hz)

Reference Example 76

A 0.35 g quantity of lithium aluminum hydride was added to 30 ml oftetrahydrofuran with ice-cooling and stirring, and ethyl[2-(3,4-dimethoxyphenyl)oxazol-4-yl]acetate obtained in ReferenceExample 75 was slowly added with stirring. After stirring at roomtemperature for 3 hours, the mixture was stirred with ice-cooling for 3hours, and 0.35 ml of water, 0.35 ml of a 15% aqueous sodium hydroxidesolution, and 1.05 ml of water were added in that order. The reactionmixture was dried over anhydrous magnesium sulfate, and insolubles werethen removed by filtration. The filtrate was concentrated under reducedpressure to give 2.5 g of colorless crystalline2-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]ethanol.

¹H-NMR (CDCl₃) δ: 7.56 (1H, d, J=8.4, 2.1 Hz), 7.52 (1H, d, J=2.1 Hz),7.46 (1H, s), 6.91 (1H, d, J=8.4 Hz), 4.17 (2H, q, J=7.2 Hz), 4.15 (2H,q, J=7.2 Hz), 3.94 (2H, q, J=5.4 Hz), 2.94 (1H, t, J=5.4 Hz), 2.81 (2H,t, J=5.4 Hz), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Reference Example 77

A 2.0 g quantity of 2-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]ethanolobtained in Reference Example 76 and 2.3 g of triphenylphosphine wereadded to 20 ml of dichloromethane, and 2.9 g of carbon tetrabromide wasslowly added with ice-cooling and stirring. After the temperature of themixture had reached room temperature, stirring was continued for 1.5hours. The reaction mixture was concentrated, and the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=8:1) to give 1.9 g of colorless crystalline4-(2-bromoethyl)-2-(3,4-diethoxyphenyl)oxazole.

¹H-NMR (CDCl₃) δ: 7.60-7.50 (3H, m), 6.91 (1H, d, J=8.4 Hz), 4.18 (2H,q, J=7.2 Hz), 4.14 (2H, q, J=7.2 Hz), 3.67 (2H, t, J=6.9 Hz), 3.14 (2H,t, J=6.9 Hz), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Reference Example 78

Using 1.5 g of 4-(2-bromoethyl)-2-(3,4-diethoxyphenyl)oxazole obtainedin Reference Example 77 and following the procedures of ReferenceExamples 6 and 7, 0.8 g of yellow oily2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]ethylamine was obtained.

¹H-NMR (CDCl₃) δ: 7.60-7.50 (3H, m), 6.91 (1H, d, J=8.4 Hz), 4.17 (2H,q, J=7.2 Hz), 4.15 (2H, q, J=7.2 Hz), 3.90-3.80 (2H, m), 3.00-2.90 (2H,m), 1.85 (2H, brs), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Reference Example 79

Using 10.4 g of 3,4-diethoxybenzamide and 19.5 g of ethyl3-bromo-2-oxopropionate and following the procedure of Reference Example5, 12.9 g of white powdery ethyl2-(3,4-diethoxyphenyl)oxazole-4-carboxylate was obtained.

¹H-NMR (CDCl₃) δ: 8.21 (1H, d, J=0.9 Hz), 7.64 (1H, dd, J=8.1, 0.9 Hz),7.63 (1H, s), 6.92 (1H, d, J=8.1 Hz), 4.42 (2H, q, J=7.2 Hz), 4.17 (2H,q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.41 (3H,t, J=7.2 Hz)

Reference Example 80

Using 10 g of the ethyl 2-(3,4-diethoxyphenyl)oxazole-4-carboxylateobtained in Reference Example 79 and following the procedure ofReference Example 71, 8.6 g of white powdery2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid was obtained.

¹H-NMR (CDCl₃) δ: 8.24 (1H, s), 7.60-7.50 (3H, m), 6.02 (1H, brs), 4.13(4H, q, J=6.9 Hz), 1.46 (3H, t, J=6.9 Hz), 1.39 (3H, t, J=6.9 Hz)

Reference Example 81

Using 0.4 g of ethyl [2-(3,4-diethoxyphenyl)oxazol-4-yl]acetate obtainedin Reference Example 75 and following the procedure of Reference Example71, 0.35 g of white powdery [2-(3,4-diethoxyphenyl)oxazol-4-yl]aceticacid was obtained.

¹H-NMR (CDCl₃) δ: 7.65-7.55 (3H, m), 7.51 (1H, d, J=2.1 Hz), 6.91 (1H,d, J=8.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 3.73 (2H,s), 1.49 (6H, t, J=6.9 Hz)

Reference Example 82

Using 3 g of4-chloromethyl-2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazoleobtained in Reference Example 23 and following the procedure ofReference Example 47, 1.91 g of colorless oily dimethyl2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}malonatewas obtained.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=8.4, 2.1 Hz), 7.60 (1H, d, J=2.1 Hz),7.42 (1H, s), 6.96 (1H, d, J=8.4 Hz), 4.44 (2H, q, J=6.9 Hz), 3.93 (3H,s), 3.89 (1H, t, J=7.5 Hz), 3.18 (2H, d, J=7.5 Hz)

Reference Example 83

Using 1.9 g of dimethyl2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}malonateobtained in Reference Example 82 and following the procedure ofReference Example 48, 1.44 g of colorless oily methyl3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propionatewas obtained.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=8.4, 2.1 Hz), 7.60 (1H, d, J=2.1 Hz),7.42 (1H, s), 6.96 (1H, d, J=8.4 Hz), 4.45 (2H, q, J=6.9 Hz), 3.92 (3H,s), 3.75 (3H, s), 2.91 (2H, t, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz)

Example 1

A 3.5 g quantity of the [2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 7 wassuspended in 70 ml of acetone. To the obtained suspension were added 2.3g of 1-hydroxybenzotriazole, 3.3 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 3.8 g of2-ethoxybenzoic acid, and the mixture was heated and refluxed for onehour. The reaction mixture was cooled, and acetone was distilled offunder reduced pressure. Water was added to the residue, and extractionwas then performed with ethyl acetate. The organic layer was washed withwater twice, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography(dichloromethane:methanol=20:1) to give 4.6 g of white powderyN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.

¹H-NMR (CDCl₃) δ: 8.55 (1H, br s) 8.23 (1H, dd, J=7.8, 1.8 Hz),7.65-7.61 (3H, m), 7.49-7.29 (6H, m), 7.09 (1H, t, J=7.5 Hz), 7.04-6.92(2H, m), 5.20 (2H, s), 4.61 (2H, d, J=5.4 Hz), 4.16 (2H, q, J=6.9 Hz),3.93 (3H, s), 1.26 (3H, t, J=6.9 Hz)

Example 2

A 4.65 g quantity of theN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamideobtained in Example 1 was dissolved in 90 ml of ethanol, and 0.45 g of10% palladium carbon powder was added thereto. The mixture was stirredin a hydrogen atmosphere at room temperature for one hour. The catalystwas removed by filtration, and the filtrate was then concentrated underreduced pressure to give 3.7 g of white crystallineN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s) 8.23 (1H, dd, J=7.8, 1.8 Hz),7.62-7.55 (3H, m), 7.41 (1H, td, J=7.5 Hz, 1.8 Hz), 7.06 (1H, t, J=7.2Hz), 6.95-6.88 (2H, m), 5.74 (1H, s), 4.62 (2H, d, J=5.1 Hz), 4.17 (2H,q, J=6.9 Hz), 3.95 (3H, s), 1.47 (3H, t, J=6.9 Hz)

Example 3

A 0.2 g quantity of the N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2 and0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml ofethanol, and 0.14 g of (bromomethyl)cyclopropane was added thereto. Themixture was heated and refluxed overnight. The reaction mixture wasallowed to cool, water was then added thereto, and extraction wasperformed with ethyl acetate. After washing with water twice, theorganic layer was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1) to give 0.18 g of white powderyN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.

¹H-NMR (CDCl₃) δ: 8.55 (1H, br s) 8.24 (1H, dd, J=7.8, 2.1 Hz),7.62-7.59 (2H, m), 7.53 (1H, d, J=2.1 Hz), 7.45-7.39 (1H, m), 7.07 (1H,td, J=8.1 Hz, 1.2 Hz), 6.95-6.91 (2H, m), 4.62 (2H, d, J=5.4 Hz), 4.18(2H, q, J=6.9 Hz), 3.94-3.92 (5H, m), 1.49 (3H, t, J=6.9 Hz), 1.42-1.34(1H, m), 0.71-0.64 (2H, m), 0.41-0.35 (2H, m)

Example 4

A 0.3 g quantity of the N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2 and0.22 g of potassium carbonate were dissolved in 10 ml ofdimethylformamide, and 0.34 g of 1,1,1-trifluoro-2-iodoethane was addedthereto. The mixture was stirred with heating at 50° C. overnight. Thereaction mixture was allowed to cool, water was then added thereto, andextraction was performed with ethyl acetate. After washing with watertwice, the organic layer was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1) to give 0.14 g of white powderyN-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamide.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s) 8.24 (1H, dd, J=7.8, 2.1 Hz), 7.73(1H, dd, J=8.4, 2.1 Hz), 7.65-7.63 (2H, m), 7.45-7.39 (1H, m), 7.09-7.01(1H, m), 6.99-6.90 (2H, m), 4.62 (2H, d, J=5.4 Hz), 4.55 (2H, q, J=8.4Hz), 4.32 (2H, q, J=6.9 Hz), 3.93 (3H, s), 1.49 (3H, t, J=6.9 Hz)

Using 0.2 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamideobtained in Example 2, compounds of Examples 5 to 14 were obtained inthe same manner as in Example 3.

Example 5 N-[2-(3-butoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 0.2 g

White Powder

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s) 8.24 (1H, dd, J=7.8, 2.1 Hz),7.62-7.54 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, t, J=8.1 Hz), 6.96-6.90(2H, m), 4.62 (2H, d, J=5.4 Hz), 4.18 (2H, q, J=6.9 Hz), 4.10 (2H, t,J=6.9 Hz), 3.92 (3H, s), 1.92-1.82 (2H, m), 1.59-1.47 (5H, m) 1.00 (3H,t, J=7.5 Hz)

Example 6N-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 0.22 g

Colorless Oily Substance

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s) 8.24 (1H, dd, J=7.8, 2.1 Hz),7.62-7.54 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, t, J=8.1 Hz), 6.96-6.90(2H, m), 4.91-4.86 (1H, m), 4.62 (2H, d, J=5.4 Hz), 4.17 (2H, q, J=6.9Hz), 3.90 (3H, s), 2.02-1.60 (8H, m), 1.49 (3H, t, J=6.9 Hz)

Example 7N-{2-[3-(3-hydroxypropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-2-ethoxybenzamide

Yield 0.12 g

White Powder

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s) 8.24 (1H, d, J=7.8 Hz), 7.62-7.54 (3H,m), 7.45-7.39 (1H, m), 7.09-7.06 (1H, m), 6.96-6.90 (2H, m), 4.62 (2H,d, J=5.4 Hz), 4.29-4.16 (4H, m), 3.92-3.79 (5H, m), 2.57 (1H, br s),2.12 (2H, t, J=5.4 Hz), 1.49 (3H, t, J=6.9 Hz)

Example 8N-[2-(4-methoxy-3-(2-propynyloxy)phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 0.19 g

White Powder

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s) 8.24 (1H, dd, J=7.8, 1.8 Hz),7.70-7.63 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, td, J=8.4, 0.9 Hz),6.98-6.93 (2H, m), 4.84 (2H, d, J=2.4 Hz), 4.63 (2H, dd, J=5.4, 0.9 Hz),4.19 (2H, q, J=7.2 Hz), 3.94 (3H, s), 2.54 (1H, t, J=2.4 Hz), 1.50 (3H,t, J=7.2 Hz)

Example 9 N-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 0.22 g

White Powdery

¹H-NMR (CDCl₃) δ: 8.55 (1H, br s) 8.24 (1H, dd, J=7.8, 1.8 Hz),7.62-7.54 (3H, m), 7.44-7.39 (1H, m), 7.07 (1H, t, J=8.1 Hz), 6.96-6.91(2H, m), 4.62 (2H, d, J=5.4 Hz), 4.23-4.14 (4H, m), 3.93 (3H, s),1.53-1.46 (6H, m)

Example 10N-[2-(4-methoxy-3-(2-oxiranylmethoxy)phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 27 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.54 (1H, br s) 8.24 (1H, dd, J=7.8, 1.8 Hz),7.67-7.58 (3H, m), 7.45-7.38 (1H, m), 7.07 (1H, t, J=7.8 Hz), 6.95 (2H,d, J=8.4 Hz), 4.62 (2H, d, J=5.1 Hz), 4.36-4.07 (4H, m), 3.93 (3H, s),3.46-3.41 (1H, m), 2.92 (1H, t, J=4.5 Hz), 2.80-2.76 (1H, m), 1.48 (3H,t, J=7.2 Hz)

Example 11 N-[2-(4-methoxy-3-propoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 0.19 g

White Powder

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s) 8.24 (1H, dd, J=7.8, 1.8 Hz),7.63-7.54 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, td, J=8.4, 1.2 Hz),6.96-6.91 (2H, m), 4.63 (2H, dd, J=5.1, 0.9 Hz), 4.18 (2H, q, J=6.9 Hz),4.06 (2H, t, J=6.9 Hz), 3.92 (3H, s), 1.97-1.85 (2H, m), 1.49 (3H, t,J=6.9 Hz), 1.07 (3H, t, J=7.2 Hz)

Example 12N-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy benzamide

Yield 0.17 g

White Powder

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s) 8.24 (1H, dd, J=7.8, 1.8 Hz),7.62-7.55 (3H, m), 7.45-7.38 (1H, m), 7.07 (1H, t, J=7.8 Hz), 6.96-6.91(2H, m), 4.72-4.59 (3H, m), 4.18 (2H, q, J=6.9 Hz), 3.91 (3H, s), 1.49(3H, t, J=6.9 Hz), 1.41 (6H, d, J=6.3 Hz)

Example 13N-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 0.21 g

White Powder

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s) 8.23 (1H, dd, J=7.8, 1.8 Hz),7.63-7.55 (3H, m), 7.45-7.38 (1H, m), 7.07 (1H, t, J=7.8 Hz), 6.96-6.91(2H, m), 5.97-5.88 (1H, m), 5.23-5.10 (2H, m), 4.62 (2H, dd, J=5.1, 0.9Hz), 4.21-4.12 (4H, m), 3.92 (3H, s), 2.68-2.60 (2H, m), 1.49 (3H, t,J=6.9 Hz)

Example 14 N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 84 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.54 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz)7.62-7.53 (2H, m), 7.44 (1H, d, J=1.8 Hz), 7.41 (2H, td, J=7.8, 1.8 Hz),7.06 (1H, t, J=7.8 Hz), 6.95-6.90 (2H, m), 4.62 (2H, d, J=5.4 Hz), 4.18(2H, q, J=6.9 Hz), 3.91 (3H, s), 3.85 (2H, d, J=6.9 Hz), 2.20 (1H, qt,J=6.9, 6.6 Hz), 1.49 (3H, t, J=6.9 Hz), 1.06 (6H, d, J=6.6 Hz)

Example 15

Using 0.2 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamideobtained in Example 2,N-{2-[4-methoxy-3-(3,3,3-trifluoropropoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamidewas obtained in the same manner as in Example 4.

Yield 60 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.55 (1H, br s) 8.23 (1H, dd, J=7.8, 1.8 Hz),7.68-7.63 (2H, m), 7.56 (1H, d, J=2.1 Hz), 7.45-7.39 (1H, m), 7.07 (1H,t, J=7.2 Hz), 6.97-6.93 (2H, m), 4.62 (2H, d, J=5.4 Hz), 4.32 (2H, t,J=6.9 Hz), 4.18 (2H, q, J=6.9 Hz), 3.92 (3H, s), 2.78-2.67 (2H, m), 1.49(3H, t, J=6.9 Hz)

Example 16

A 1.5 g quantity of the [2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 7 wassuspended in 30 ml of acetone. To the obtained suspension were added 1.0g of 1-hydroxybenzotriazole, 1.4 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.8 g of3-methylpicolinic acid, and the mixture was heated and refluxed for 30minutes. The reaction mixture was cooled, and acetone was distilled offunder reduced pressure. Water was added to the residue, and extractionwas then performed with ethyl acetate. The organic layer was washed withwater twice, and the solvent was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(dichloromethane:methanol=20:1) to give 1.5 g of white powderyN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.39 (1H, d, J=7.5 Hz), 7.65-7.28(10H, m), 6.94 (1H, d, J=9.0 Hz), 5.21 (2H, s), 4.58 (2H, dd, J=5.7, 0.9Hz), 3.93 (3H, s), 2.76 (3H, s)

Example 17

A 1.5 g quantity of the N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 16was dissolved in 50 ml of ethanol, and 0.1 g of 10% palladium carbonpowder was added thereto. The mixture was stirred in a hydrogenatmosphere at 50° C. for two hours. The catalyst was removed byfiltration, and the filtrate was then concentrated to give 1.3 g ofwhite crystallineN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.38 (1H, dd, J=4.5, 0.9 Hz), 7.63(1H, s), 7.62-7.54 (3H, m), 7.32-7.27 (1H, m), 6.90 (1H, d, J=8.4 Hz),5.75 (1H, br s), 4.58 (2H, dd, J=6.0, 0.9 Hz), 3.94 (3H, s), 2.75 (3H,s)

Example 18

A 0.15 g quantity of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamideobtained in Example 17 and 0.5 ml of 1,8-diazabicyclo[5,4,0]undec-7-enewere dissolved in 4 ml of ethanol, and 0.13 g of bromocyclopentane wasadded thereto. The mixture was heated and refluxed for 3 hours. Thereaction mixture was allowed to cool, water was then added thereto, andextraction was performed with ethyl acetate. The extract was washed withwater twice, and the organic layer was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to give 0.11 g of whitepowderyN-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.39 (1H, dd, J=4.8, 0.9 Hz),7.62-7.53 (4H, m), 7.32-7.27 (1H, m), 6.91 (1H, d, J=8.4 Hz), 4.88 (1H,tt, J=3.3 Hz), 4.59 (2H, dd, J=5.7, 0.9 Hz), 3.89 (3H, s), 2.76 (3H, s),2.07-1.79 (6H, m), 1.70-1.60 (2H, m)

Example 19

A 0.15 g quantity of the N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17and 0.18 g of potassium carbonate were dissolved in 4 ml ofdimethylformamide, and 0.19 g of 1,1,1-trifluoro-2-iodoethane was addedthereto. The mixture was stirred with heating at 80° C. overnight. Thereaction mixture was allowed to cool, water was then added thereto, andextraction was performed with ethyl acetate. The extract was washed withwater twice, and the organic layer was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to give 0.11 g of whitepowderyN-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, dd, J=4.5, 1.2 Hz), 7.73(1H, dd, J=8.7, 2.1 Hz), 7.63-7.57 (3H, m), 7.32-7.27 (1H, m), 6.97 (1H,d, J=8.4 Hz), 4.59 (2H, dd, J=5.7, 0.9 Hz), 4.46 (2H, q, J=8.4 Hz), 3.93(3H, s), 2.76 (3H, s)

Example 20

Using 0.2 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamideobtained in Example 17, 0.11 g ofN-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained in the same manner as in Example 3.

Colorless Crystals

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.39 (1H, dd, J=4.8, 1.5 Hz),7.65-7.50 (4H, m), 7.30 (1H, dd, J=7.8, 4.8 Hz), 6.92 (1H, d, J=8.1 Hz),4.59 (1H, dd, J=6.0, 0.6 Hz), 4.19 (2H, q, J=6.9 Hz), 4.17 (2H, q, J=6.9Hz), 3.92 (3H, s), 2.76 (3H, s), 1.50 (3H, t, J=6.9 Hz)

Example 21

Using 0.15 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamideobtained in Example 17, 45 mg ofN-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained in the same manner as in Example 3.

Colorless Crystal

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, dd, J=4.5, 1.5 Hz),7.65-7.50 (4H, m), 7.30 (1H, dd, J=7.8, 4.5 Hz), 6.93 (1H, d, J=8.4 Hz),6.12 (1H, m), 5.45 (1H, m), 5.32 (1H, dd, J=9.6, 1.5 Hz), 4.70 (2H, d,J=5.4 Hz), 4.59 (1H, d, J=6.0 Hz), 3.92 (3H, s), 2.76 (3H, s).

Example 22

A 170 mg quantity of the N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17was dissolved in 10 ml of tetrahydrofuran. To the obtained solution wereadded 134 mg of 2-hydroxyindane, 0.5 ml of diisopropyl azodicarboxylate(40% toluene solution) and 202 mg of tri(n-butyl)phosphine, and themixture was stirred at room temperature overnight, and at 50° C. for 2.5hours. To the reaction mixture were added 100 mg of 2-hydroxyindane, 0.5ml of diisopropyl azodicarboxylate (40% toluene solution) and 200 mg oftri(n-butyl)phosphine, and the mixture was stirred at 50° C. for 5hours, and at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate:methylenechloride=1:1:1) to give 92 mg ofN-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-3-methylpicolinamide.

Pale Yellow Oily Substance

¹H-NMR (CDCl₃) δ: 8.59 (1H, br s), 8.39 (1H, d, J=3.3 Hz), 7.65-7.16(9H, m), 6.93 (1H, d, J=8.1 Hz), 5.30 (1H, tt, J=6.6, 3.9 Hz), 4.60 (2H,d, J=5.7 Hz), 3.86 (3H, s), 3.46 (2H, dd, J=16.8, 6.6 Hz), 3.27 (2H, dd,J=16.8, 3.9 Hz), 2.76 (3H, s)

Example 23

Using 0.88 g of the[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained inReference Example 7, 1.03 g of white powderyN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 7.72-7.46 (9H, m), 7.40-7.27 (3H, m), 6.95 (1H, d,J=8.4 Hz) 6.34 (1H, br s), 5.20 (2H, s), 4.59 (2H, d, J=5.4 Hz), 3.93(3H, s)

Example 24

Using 1.0 g of theN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamideobtained in Example 23, 0.66 g of white powderyN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamide was obtained in the samemanner as in Example 2.

¹H-NMR (CDCl₃) δ: 7.71-7.50 (7H, m), 6.90 (1H, d, J=8.4 Hz), 6.39 (1H,br s), 5.76 (1H, s), 4.59 (2H, d, J=5.4 Hz), 3.94 (3H, s)

Example 25

Using 0.2 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamideobtained in Example 24, 0.18 g of white powderyN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamidewas obtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 7.72-7.50 (7H, m), 6.93 (1H, d, J=8.4 Hz), 6.34 (1H,s), 4.60 (2H, d, J=5.4 Hz), 3.93 (3H, s), 1.42-1.32 (1H, m), 0.70-0.63(2H, m), 0.41-0.35 (2H, m)

Example 26

Using 0.2 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamideobtained in Example 24, 40 mg of white powderyN-{2-[3-(3-hydroxypropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-2-trifluoromethylbenzamidewas obtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 7.71-7.50 (7H, m), 6.92 (1H, d, J=8.4 Hz), 6.34 (1H,br s), 4.60 (2H, d, J=5.4 Hz), 4.28 (2H, q, J=5.7 Hz), 3.98-3.86 (5H,m), 2.47 (1H, t, J=5.7 Hz), 2.15-2.07 (3H, m)

Example 27

Using 0.5 g of the2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained inReference Example 7, 0.62 g of white powderyN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.24-8.22 (2H, m), 7.64-7.60 (3H, m), 7.50-7.46 (2H,m), 7.41-7.28 (5H, m), 6.94 (1H, d, J=9.0 Hz), 5.20 (2H, s), 4.61 (2H,d, J=5.7 Hz), 4.17 (2H, q, J=6.9 Hz), 3.93 (3H, s), 1.50 (3H, t, J=6.9Hz)

Example 28

Using 0.6 g of theN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamideobtained in Example 27, 0.5 g of white amorphousN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamidewas obtained in the same manner as in Example 2.

¹H-NMR (CDCl₃) δ: 8.25-8.22 (2H, m), 7.64 (1H, d, J=1.8 Hz), 7.60-7.54(2H, m), 7.39-7.28 (2H, m), 6.91 (1H, d, J=8.1 Hz), 5.71 (1H, br s),4.61 (2H, dd, J=5.4, 0.9 Hz), 4.17 (2H, q, J=6.9 Hz), 3.94 (3H, s), 1.52(3H, t, J=6.9 Hz)

Example 29

Using 0.5 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamideobtained in Example 28, 0.18 g of white amorphousN-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamidewas obtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 8.25-8.22 (2H, m), 7.64 (1H, s), 7.58 (1H, dd, J=8.4,2.1 Hz), 7.53 (1H, d, J=1.8 Hz), 7.39-7.32 (2H, m), 6.91 (1H, d, J=8.4Hz), 4.91-4.86 (1H, m), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.17 (2H, q, J=6.9Hz), 3.89 (3H, s), 2.05-1.79 (6H, m), 1.66-1.60 (2H, m), 1.51 (3H, t,J=6.9 Hz)

Example 30

Using 0.31 g of the2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained inReference Example 7, 0.16 g of white powderyN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroethoxy)benzamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.22 (1H, dd, J=7.8, 1.8 Hz), 7.82 (1H, br s),7.63-7.60 (3H, m), 7.49-7.27 (6H, m), 7.19 (1H, t, J=7.2 Hz), 6.96-6.88(2H, m), 5.19 (2H, s), 4.62 (2H, d, J=5.4 Hz), 4.47 (2H, q, J=7.8 Hz),3.92 (3H, s)

Example 31

Using 0.16 g of theN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroethoxy)benzamideobtained in Example 30, 0.11 g of white powderyN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroethoxy)benzamide wasobtained in the same manner as in Example 2.

¹H-NMR (CDCl₃) δ: 8.21 (1H, dd, J=7.8, 1.8 Hz), 7.84 (1H, br s),7.62-7.54 (3H, m), 7.49-7.43 (1H, m), 7.19 (1H, td, J=7.8, 0.9 Hz), 5.71(1H, s), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.48 (2H, q, J=7.8 Hz), 3.94 (3H,s)

Example 32

Using 0.11 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroethoxy)benzamideobtained in Example 31, 78 mg of white amorphousN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-(2,2,2-trifluoroethoxy)benzamidewas obtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 8.22 (1H, dd, J=7.8, 2.1 Hz), 7.83 (1H, br s),7.61-7.57 (3H, m), 7.53 (1H, d, J=2.1 Hz), 7.50-7.43 (1H, m), 7.19 (1H,td, J=7.8, 0.9 Hz), 6.94-6.88 (2H, m), 4.63 (2H, dd, J=5.4, 0.9 Hz),4.48 (2H, q, J=7.8 Hz), 1.42-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35(2H, m)

Example 33

Using 0.5 g of the2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained inReference Example 7, 0.68 g of pale yellow powderyN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.39 (1H, br s), 8.23 (1H, dd, J=4.8, 1.8 Hz),7.65-7.60 (3H, m), 7.50-7.28 (6H, m), 7.08 (1H, t, J=7.2 Hz), 6.98-6.93(2H, m), 5.21 (2H, s), 4.61 (2H, dd, J=5.4, 0.9 Hz), 3.95 (3H, s), 3.93(3H, s)

Example 34

Using 0.67 g of theN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamideobtained in Example 33, 0.52 g of white amorphousN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamidewas obtained in the same manner as in Example 2.

¹H-NMR (CDCl₃) δ: 8.43 (1H, br s), 8.23 (1H, dd, J=7.8, 2.1 Hz), 7.63(1H, s), 7.60-7.54 (2H, m), 7.47-7.41 (1H, m), 7.10-7.05 (1H, m), 6.97(1H, d, J=8.4 Hz), 6.91 (1H, d, J=8.1 Hz), 5.74 (1H, br s), 4.62 (2H,dd, J=5.4, 0.9 Hz), 3.97 (3H, s), 3.95 (3H, s)

Example 35

Using 0.5 g of theN-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamideobtained in Example 34, 0.39 g of white powderyN-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamidewas obtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 8.41 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz), 7.63(1H, s), 7.59 (1H, dd, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz), 7.48-7.42(1H, m), 7.08 (1H, t, J=7.8 Hz), 6.98 (1H, d, J=8.1 Hz), 6.92 (1H, d,J=8.4 Hz), 4.91-4.87 (1H, m), 4.62 (2H, dd, J=5.4, 0.9 Hz), 3.97 (3H,s), 3.90 (3H, s), 2.05-1.80 (6H, m), 1.66-1.59 (2H, m)

Example 36

A 0.2 g quantity of the[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamineobtained in Reference Example 13 was suspended in 4 ml of acetone. Tothe obtained suspension were added 0.2 g of 1-hydroxybenzotriazole, 0.29g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and0.14 g of 3-methylpicolinic acid, and the mixture was heated andrefluxed for 30 minutes. The reaction mixture was cooled, water was thenadded thereto, and extraction was performed with ethyl acetate. Theorganic layer was washed with water twice, and the solvent wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give0.16 g of white powderyN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s) 8.39 (1H, dd, J=4.5, 1.2 Hz),7.63-7.57 (3H, m), 7.52 (1H, d, J=2.1 Hz), 7.33-7.28 (1H, m), 6.92 (1H,d, J=8.4 Hz), 4.59 (2H, dd, J=6.0, 0.9 Hz), 3.97-3.90 (5H, m), 2.76 (3H,s), 1.41-1.31 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Using 0.2 g of the [2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,compounds of Examples 37 to 43 were obtained in the same manner as inExample 1.

Example 37N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isopropoxybenzamide

Yield 0.17 g

White Powder

¹H-NMR (CDCl₃) δ: 8.62 (1H, br s) 8.23 (1H, dd, J=7.8, 1.8 Hz),7.62-7.58 (2H, m), 7.54 (1H, d, J=2.1 Hz), 7.43-7.38 (1H, m), 7.05 (1H,td, J=8.1, 0.9 Hz), 6.97-6.91 (2H, m), 4.76-4.67 (1H, m), 4.61 (2H, dd,J=5.4, 0.9 Hz), 3.94-3.90 (5H, m), 1.41-1.38 (7H, m), 0.69-0.64 (2H, m),0.41-0.35 (2H, m)

Example 38N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylbenzamide

Yield 0.16 g

White Powder

¹H-NMR (CDCl₃) δ: 7.64 (1H, s) 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H,d, J=2.1 Hz), 7.41-7.16 (3H, m), 6.93 (1H, d, J=8.4 Hz), 6.31 (1H, brs), 4.58 (2H, dd, J=5.4, 0.9 Hz), 3.95-3.92 (5H, m), 2.46 (3H, s),1.42-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 39N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethylbenzamide

Yield 0.15 g

White Powder

¹H-NMR (CDCl₃) δ: 7.64 (1H, s) 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H,d, J=1.8 Hz), 7.41-7.16 (3H, m), 6.93 (1H, d, J=8.1 Hz), 6.31 (1H, brs), 4.57 (2H, d, J=5.4 Hz), 3.95-3.92 (5H, m), 2.81 (2H, q, J=7.5 Hz),1.42-1.32 (1H, m), 1.23 (3H, t, J=7.5 Hz), 0.70-0.63 (2H, m), 0.41-0.35(2H, m)

Example 40N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-chlorobenzamide

Yield 0.17 g

White Powder

¹H-NMR (CDCl₃) δ: 7.71-7.66 (2H, m), 7.59 (1H, dd, J=8.4, 1.8 Hz), 7.50(1H, d, J=2.1 Hz), 7.42-7.29 (3H, m), 6.93 (1H, d, J=8.4 Hz), 6.75 (1H,br s), 4.62 (2H, dd, J=5.4, 0.9 Hz), 3.95-3.92 (5H, m), 1.41-1.32 (1H,m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 41N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-5-fluoro-2-methoxybenzamide

Yield 0.19 g

White Powder

¹H-NMR (CDCl₃) δ: 8.45 (1H, br s), 7.94 (1H, dd, J=9.6, 3.3 Hz), 7.63(1H, s), 7.61 (1H, dd, J=8.1, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.17-7.10(1H, m), 6.95-6.90 (2H, m), 4.61 (2H, d, J=5.4 Hz), 3.96-3.92 (8H, m),1.40-1.30 (1H, m), 0.70-0.64 (2H, m), 0.41-0.35 (2H, m)

Example 42N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-4-fluoro-2-methoxybenzamide

Yield 0.19 g

White Powder

¹H-NMR (CDCl₃) δ: 8.27-8.21 (2H, m), 7.63-7.58 (2H, m), 7.52 (1H, d,J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz), 6.81-6.74 (1H, m), 6.69 (1H, dd,J=10.2, 2.1 Hz), 4.60 (2H, dd, J=5.4, 0.9 Hz), 3.97-3.90 (8H, m),1.40-1.30 (1H, m), 0.70-0.64 (2H, m), 0.41-0.35 (2H, m)

Example 43N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-fluoro-6-methoxybenzamide

Yield 0.17 g

White Powder

¹H-NMR (CDCl₃) δ: 7.65 (1H, s), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H,d, J=2.1 Hz), 7.34-7.27 (1H, m), 6.92 (1H, d, J=8.4 Hz), 6.76-6.70 (2H,m), 6.51 (1H, br s), 4.61 (2H, d, J=5.7 Hz), 3.94-3.91 (5H, m), 3.85(3H, s), 1.42-1.31 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 44

Using 0.4 g of the [2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylsulfanylbenzamidewas obtained in the same manner as in Example 1.

Yield 0.4 g

White Powder

¹H-NMR (CDCl₃) δ: 7.68 (1H, s), 7.61-7.56 (2H, m), 7.50 (1H, d, J=1.8Hz), 7.34-7.17 (3H, m), 6.95-6.90 (2H, m), 4.61 (2H, dd, J=5.4, 0.9 Hz),3.95-3.92 (5H, m), 2.46 (3H, s), 1.42-1.31 (1H, m), 0.70-0.63 (2H, m),0.41-0.35 (2H, m)

Example 45

Using 0.7 g of the [2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-hydroxypicolinamidewas obtained in the same manner as in Example 1.

Yield 0.6 g

White Powder

¹H-NMR (CDCl₃) δ: 12.02 (1H, s), 8.45 (1H, br s), 8.06 (1H, dd, J=4.2,1.8 Hz), 7.63-7.59 (2H, m), 7.52 (1H, s), 7.37-7.29 (3H, m), 6.93 (1H,d, J=8.4 Hz), 4.60 (2H, d, J=6.0 Hz), 3.96-3.93 (5H, m), 1.56-1.33 (1H,m), 0.70-0.64 (2H, m), 0.42-0.36 (2H, m)

Using 0.1 g of the [2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 13,compounds of Examples 46 to 56 were obtained in the same manner as inExample 1.

Example 46N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamide

Yield 0.1 g

White Powder

¹H-NMR (CDCl₃) δ: 8.40 (1H, br s), 8.23 (1H, dd, J=7.8, 2.1 Hz)7.64-7.58 (2H, m), 7.52 (1H, d, J=2.1 Hz), 7.48-7.42 (1H, m), 7.08 (1H,td, J=7.8, 0.9 Hz), 6.99-6.91 (2H, m), 4.62 (2H, dd, J=5.4, 0.9 Hz),3.97-3.91 (8H, m), 1.40-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H,m)

Example 47N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethoxybenzamide

Yield 43 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.02 (1H, dd, J=7.8, 1.8 Hz), 7.64-7.27 (6H, m), 7.10(1H, br s), 6.93 (1H, d, J=8.4 Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz),3.95-3.92 (5H, m), 1.43-1.28 (1H, m), 0.69-0.63 (2H, m), 0.41-0.36 (2H,m)

Example 48N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-propoxybenzamide

Yield 0.1 g

White Powder

¹H-NMR (CDCl₃) δ: 8.50 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz)7.61-7.58 (2H, m), 7.53 (1H, d, J=1.8 Hz), 7.44-7.38 (1H, m), 7.06 (1H,t, J=7.8 Hz), 6.95-6.91 (2H, m), 4.62 (2H, d, J=5.1 Hz), 4.06 (2H, t,J=6.6 Hz), 3.95-3.68 (5H, m), 1.86 (2H, td, J=7.5, 6.6 Hz), 1.41-1.31(1H, m), 0.96 (3H, t, J=7.5 Hz), 0.70-0.61 (2H, m), 0.41-0.35 (2H, m)

Example 49N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]pyrazine-2-carboxamide

Yield 90 mg

White Powder

¹H-NMR (CDCl₃) δ: 9.42 (1H, s), 8.75 (1H, d, J=2.4 Hz), 8.52 (1H, dd,J=2.7, 1.5 Hz), 8.25 (1H, br s), 7.64 (1H, s), 7.60 (1H, dd, J=8.4, 1.8Hz), 7.52 (1H, d, J=1.8 Hz), 6.92 (1H, d, J=8.4 Hz), 4.63 (2H, dd,J=5.4, 0.9 Hz), 4.11-3.92 (5H, m), 1.40-1.32 (1H, m), 0.70-0.63 (2H, m),0.41-0.35 (2H, m)

Example 50N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamide

Yield 85 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.24-8.22 (2H, m) 7.64 (1H, s), 7.60 (1H, dd, J=8.4,1.8 Hz), 7.51 (1H, d, J=2.1 Hz), 7.39-7.32 (2H, m), 6.92 (1H, d, J=8.4Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.17 (2H, q, J=6.9 Hz), 3.98-3.92(5H, m), 1.52 (3H, t, J=6.9 Hz), 1.43-1.32 (1H, m), 0.71-0.63 (2H, m),0.41-0.35 (2H, m)

Example 51N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-butoxybenzamide

Yield 70 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.48 (1H, br s) 8.23 (1H, dd, J=7.8, 1.8 Hz),7.63-7.59 (2H, m), 7.53 (1H, d, J=2.1 Hz), 7.45-7.38 (1H, m), 7.06 (1H,td, J=8.4, 0.9 Hz), 6.96-6.91 (2H, m), 4.61 (2H, d, J=5.1 Hz), 4.09 (2H,t, J=6.6 Hz), 3.94-3.91 (5H, m), 1.84-1.75 (2H, m), 1.46-1.33 (3H, m),0.84 (3H, t, J=7.2 Hz), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 52N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isobutoxybenzamide

Yield 0.12 g

White Powder

¹H-NMR (CDCl₃) δ: 8.46 (1H, br s) 8.24 (1H, dd, J=7.8, 1.8 Hz),7.62-7.58 (2H, m), 7.52 (1H, d, J=1.8 Hz), 7.41 (1H, t, J=7.2 Hz), 7.06(1H, t, J=7.2 Hz), 6.95-6.91 (2H, m), 4.62 (2H, d, J=5.1 Hz), 3.95-3.92(5H, m), 3.86 (2H, d, J=6.3 Hz), 2.20-2.10 (1H, m), 1.40-1.31 (1H, m),0.95 (6H, d, J=6.6 Hz), 0.70-0.63 (2H, m), 0.41-0.37 (2H, m)

Example 53N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isopropoxypicolinamide

Yield 0.1 g

White Powder

¹H-NMR (CDCl₃) δ: 8.28-8.25 (2H, m) 7.63 (1H, s), 7.60 (1H, dd, J=8.4,2.1 Hz), 7.52 (1H, d, J=2.1 Hz), 7.38-7.31 (2H, m), 6.93 (1H, d, J=8.4Hz), 4.70-4.61 (3H, m), 3.98-3.90 (5H, m), 1.42-1.31 (7H, m), 0.70-0.61(2H, m), 0.41-0.35 (2H, m)

Example 54N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethylsulfanylbenzamide

Yield 85 mg

White Powder

¹H-NMR (CDCl₃) δ: 7.70-7.66 (2H, m), 7.59 (1H, dd, J=8.4, 1.8 Hz), 7.51(1H, d, J=2.1 Hz), 7.43-7.32 (2H, m), 7.27-7.22 (2H, m), 6.92 (1H, d,J=8.7 Hz), 4.61 (2H, dd, J=5.4, 0.6 Hz), 3.95-3.92 (5H, m), 2.90 (2H, q,J=7.5 Hz), 1.40-1.34 (1H, m), 1.26 (3H, t, J=7.2 Hz), 0.70-0.63 (2H, m),0.41-0.35 (2H, m)

Example 55N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-1-oxidepicolinamide

Yield 53 mg

Pale Yellow Powder

¹H-NMR (CDCl₃) δ: 11.64 (1H, br s), 8.44 (1H, dd, J=7.8, 2.1 Hz), 8.25(1H, d, J=6.3 Hz), 7.63-7.35 (5H, m), 6.91 (1H, d, J=8.7 Hz), 4.65 (2H,d, J=5.7 Hz), 3.97-3.88 (5H, m), 1.43-1.32 (1H, m), 0.70-0.63 (2H, m),0.41-0.36 (2H, m)

Example 56N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2,6-dimethoxybenzamide

Yield 46 mg

White Powder

¹H-NMR (CDCl₃) δ: 7.67 (1H, s), 7.59 (1H, dd, J=8.4, 1.8 Hz), 7.50 (1H,d, J=2.1 Hz), 7.30-7.24 (1H, m), 6.92 (1H, d, J=8.4 Hz), 6.56 (2H, d,J=8.4 Hz), 6.24 (1H, br s), 4.62 (2H, dd, J=5.7, 0.9 Hz), 3.95-3.92 (5H,m), 3.81 (6H, s), 1.41-1.32 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H,m)

Using 0.13 g of [2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine, compounds of Examples 57 to 59 wereobtained in the same manner as in Example 1.

Example 57N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methoxypicolinamide

Yield 24 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.23-8.19 (2H, m) 7.65 (1H, s), 7.59 (1H, dd, J=8.4,2.1 Hz), 7.51 (1H, d, J=1.8 Hz), 7.43-7.34 (2H, m), 6.92 (1H, d, J=8.7Hz), 4.60 (2H, d, J=5.4 Hz), 3.96-3.93 (8H, m), 1.43-1.30 (1H, m),0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 58N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isobutoxypicolinamide

Yield 0.11 g

White Powder

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=3.9, 1.8 Hz), 8.17 (1H, br s), 7.63(1H, s), 7.59 (1H, dd, J=8.4, 1.8 Hz), 7.38-7.31 (2H, m), 6.92 (1H, d,J=8.4 Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz), 3.95-3.92 (5H, m), 3.84 (2H, d,J=6.3 Hz), 2.20 (1H, qt, J=6.6 Hz), 1.40-1.34 (1H, m), 1.03 (6H, d,J=6.6 Hz), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 59N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylnicotinamide

Yield 71 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.55 (1H, dd, J=7.8, 1.8 Hz), 7.71 (1H, dd, J=7.5, 1.8Hz), 7.65 (1H, s), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.17-7.13 (1H, m), 6.93(2H, d, J=8.4 Hz), 6.35 (1H, br s), 4.58 (2H, dd, J=5.4, 0.9 Hz),3.96-3.91 (5H, m), 2.69 (3H, s), 1.41-1.31 (1H, m), 0.70-0.63 (2H, m),0.41-0.35 (2H, m)

Example 60

0.4 g ofN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylsulfanylbenzamideobtained in Example 44 was dissolved in 20 ml of dichloromethane, and0.67 g of metachloroperbenzoic acid was added thereto while the solutionwas cooled with ice with stirring. The mixture was then stirred for anhour. The reaction mixture was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography (NH silica,n-hexane:ethyl acetate=1:1), and 50 mg of white powderyN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methanesulfonylbenzamide was obtained.

¹H-NMR (CDCl₃) δ: 8.11 (1H, dd, J=7.8, 0.9 Hz), 7.76 (1H, s), 7.69-7.55(4H, m), 7.50 (1H, d, J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz), 6.50 (1H, brs), 4.62 (2H, d, J=5.4 Hz), 3.95-3.90 (5H, m), 3.93-3.67 (1H, m), 3.37(3H, s), 1.40-1.32 (1H, m), 1.27-1.18 (3H, m), 0.70-0.63 (2H, m),0.41-0.35 (2H, m)

Example 61

0.1 g ofN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-hydroxypicolinamideobtained in Example 45 and 0.16 g of cesium carbonate were dissolved in4 ml of acetonitrile, and 0.2 g of 1-bromopropane was added thereto andstirred overnight at room temperature. Water was added to the reactionmixture and extraction was performed with ethyl acetate. The extract waswashed with water once, and further washed with saturated aqueous citricacid once. The organic layer was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography, yielding 72 mg of white powderyN-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-propoxypicolinamide.

¹H-NMR (CDCl₃) δ: 8.25-8.20 (2H, m) 7.64 (1H, s), 7.60 (1H, dd, J=8.4,1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.39-7.32 (2H, m), 6.92 (1H, d, J=8.4Hz), 4.62 (2H, dd, J=5.7, 0.9 Hz), 4.05 (2H, t, J=6.6 Hz), 3.94-3.92(5H, m), 1.90 (2H, t, J=7.5, 6.6 Hz), 1.40-1.33 (1H, m), 1.04 (3H, t,J=7.5 Hz), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 62

Using 0.18 g of [2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]methylamineobtained in Reference Example 19, 0.16 g of white powderyN-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s) 8.39 (1H, dd, J=4.5, 1.8 Hz), 7.63(1H, s), 7.62-7.59 (2H, m), 7.57 (1H, d, J=0.9 Hz), 7.32-7.27 (1H, m),6.92 (1H, d, J=8.4 Hz), 4.59 (2H, dd, J=6.0, 0.9 Hz), 3.91 (3H, s), 3.86(2H, d, J=6.9 Hz), 2.76 (3H, s), 2.20 (1H, qt, J=6.9, 6.6 Hz), 1.06 (6H,d, J=6.6 Hz)

Using 0.15 g of [2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]methylamineobtained in Reference Example 19, compounds of Examples 63 to 75 wereobtained in the same manner as in Example 1.

Example 63N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxybenzamide

Yield 0.12 g

White Powder

¹H-NMR (CDCl₃) δ: 8.41 (1H, br s) 8.23 (1H, dd, J=7.8, 1.8 Hz), 7.64(1H, s), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.53 (1H, d, J=2.1 Hz), 7.48-7.42(1H, m), 7.11-6.90 (3H, m), 4.63 (2H, dd, J=5.4, 0.9 Hz), 3.97 (3H, s),3.91 (3H, s), 3.86 (2H, d, J=6.9 Hz), 2.21 (1H, qt, J=6.6 Hz), 1.06 (6H,d, J=6.6 Hz)

Example 64 N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylsulfanylbenzamide

Yield 0.15 g

White Powder

¹H-NMR (CDCl₃) δ: 7.69 (1H, s), 7.61-7.56 (2H, m), 7.51 (1H, d, J=1.8Hz), 7.45-7.15 (3H, m) 6.94-6.90 (2H, m), 4.61 (2H, d, J=5.7 Hz), 3.91(3H, s), 3.85 (2H, d, J=6.9 Hz), 2.46 (3H, s), 2.20 (1H, qt, J=6.9 Hz),1.06 (6H, d, J=6.9 Hz)

Example 65 N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-ethoxypicolinamide

Yield 80 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.25-8.22 (2H, m) 7.65 (1H, s), 7.58 (1H, dd, J=8.4,1.8 Hz), 7.52 (1H, d, J=1.8 Hz), 7.40-7.32 (2H, m), 6.92 (1H, d, J=8.4Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.18 (2H, q, J=6.9 Hz), 3.91 (3H, s),3.86 (2H, d, J=6.9 Hz), 2.20 (1H, qt, J=6.9 Hz), 1.52 (3H, t, J=6.9 Hz),1.06 (6H, d, J=6.6 Hz)

Example 66N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methoxy-4-fluorobenzamide

Yield 0.11 g

White Powder

¹H-NMR (CDCl₃) δ: 8.27-8.21 (2H, m), 7.63 (1H, s), 7.59 (1H, dc, J=8.4,2.1 Hz), 7.52 (1H, d, J=2.1 Hz), 6.93 (1H, d, J=8.4 Hz), 6.81-6.74 (1H,m), 6.69 (1H, dd, J=10.5, 2.4 Hz), 4.61 (2H, dd, J=5.4, 0.9 Hz), 3.96(3H, s), 3.91 (3H, s), 3.85 (2H, d, J=6.6 Hz), 2.20 (1H, qt, J=6.9, 6.6Hz), 1.06 (6H, d, J=6.6 Hz)

Example 67N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isopropoxybenzamide

Yield 0.15 g

Colorless Oily Substance

¹H-NMR (CDCl₃) δ: 8.64 (1H, br s) 8.24 (1H, dd, J=7.8, 1.8 Hz),7.62-7.57 (2H, m), 7.54 (1H, d, J=1.8 Hz), 7.44-7.37 (1H, m), 7.08-7.02(1H, m), 6.98-6.91 (2H, m), 4.72 (1H, q, J=6.0 Hz), 4.62 (2H, dd, J=5.1,0.9 Hz), 3.92 (3H, s), 3.85 (2H, d, J=6.6 Hz), 2.20 (1H, qt, J=6.6 Hz),1.40 (6H, d, J=6.0 Hz), 1.06 (6H, d, J=6.6 Hz)

Example 68N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-fluoro-6-methoxybenzamide

Yield 0.13 g

White Powder

¹H-NMR (CDCl₃) δ: 7.65 (1H, d, J=0.9 Hz), 7.58 (1H, dd, J=8.4, 2.1 Hz),7.51 (1H, d, J=2.1 Hz), 7.34-7.24 (1H, m), 6.92 (1H, d, J=8.4 Hz),6.77-6.70 (2H, m), 6.52 (1H, br s), 4.62 (2H, dd, J=5.7, 0.9 Hz), 3.91(3H, s), 3.90-3.82 (5H, m), 2.20 (1H, qt, J=6.9 Hz), 1.06 (6H, d, J=6.9Hz)

Example 69N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methoxypicolinamide

Yield 0.14 g

White Powder

¹H-NMR (CDCl₃) δ: 8.19-8.22 (2H, m), 7.65 (1H, s), 7.58 (1H, dd, J=8.4,1.8 Hz), 7.52 (1H, d, J=2.1 Hz), 7.43-7.34 (1H, m), 6.92 (1H, d, J=8.4Hz), 4.61 (2H, dd, J=5.7, 0.9 Hz), 3.96 (3H, s), 3.91 (3H, s), 3.86 (2H,d, J=6.6 Hz), 2.20 (1H, qt, J=6.9, 6.6 Hz), 1.06 (6H, d, J=6.9 Hz)

Example 70N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isobutoxypicolinamide

Yield 68 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=3.9, 2.1 Hz), 8.17 (1H, br s), 7.64(1H, s), 7.58 (1H, dd, J=8.4, 2.1 Hz), 7.52 (1H, d, J=1.8 Hz), 7.38-7.28(2H, m), 6.92 (2H, d, J=8.4 Hz), 4.63 (2H, dd, J=5.4, 0.9 Hz), 3.91 (3H,s), 3.87-3.82 (4H, m), 2.27-2.13 (2H, m), 1.07-1.02 (2H, m)

Example 71N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-propoxy benzamide

Yield 75 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.52 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz),7.62-7.58 (2H, m), 7.53 (1H, s), 7.42 (1H, td, J=7.2, 1.8 Hz), 7.06 (1H,t, J=7.8 Hz), 6.95-6.91 (2H, m), 4.62 (2H, d, J=5.1 Hz), 4.06 (2H, t,J=6.6 Hz), 3.94 (3H, s), 3.85 (2H, d, J=6.6 Hz), 2.24-2.16 (1H, m),1.93-1.81 (2H, m), 1.06 (6H, d, J=6.6 Hz), 0.97 (3H, t, J=7.2 Hz)

Example 72 N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-butoxybenzamide

Yield 47 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.48 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz),7.62-7.58 (2H, m), 7.53 (1H, s), 7.42 (1H, td, J=7.2, 1.8 Hz), 7.06 (1H,t, J=7.8 Hz), 6.95-6.91 (2H, m), 4.61 (2H, d, J=5.1 Hz), 4.10 (2H, t,J=6.6 Hz), 3.91 (3H, s), 3.85 (2H, d, J=6.6 Hz), 2.24-2.16 (1H, m),1.85-1.75 (2H, m), 1.43-1.36 (2H, m), 1.05 (6H, d, J=6.6 Hz), 0.84 (3H,t, J=7.2 Hz)

Example 73N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-isobutoxybenzamide

Yield 90 mg

White Powder

¹H-NMR (CDCl₃) δ: 8.52 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz),7.62-7.58 (2H, m), 7.53 (1H, s), 7.42 (1H, td, J=7.2, 1.8 Hz), 7.06 (1H,t, J=7.8 Hz), 6.93-6.90 (2H, m), 4.62 (2H, d, J=5.1 Hz), 3.91 (3H, s),3.87-3.83 (4H, m), 2.24-2.16 (2H, m), 1.06 (6H, d, J=6.6 Hz), 0.95 (6H,d, J=6.6 Hz)

Example 74N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-isopropoxypicolinamide

Yield 0.11 g

White Powder

¹H-NMR (CDCl₃) δ: 8.52 (1H, br s), 8.27 (1H, br s), 7.63 (1H, s), 7.58(1H, dd, J=7.8, 1.8 Hz), 7.53 (1H, s), 7.35-7.34 (2H, m), 6.92 (1H, d,J=8.4 Hz), 4.67-4.61 (3H, m), 3.91 (3H, s), 3.85 (2H, d, J=6.6 Hz),2.22-2.17 (1H, m), 1.42 (6H, d, J=6.6 Hz), 1.06 (6H, d, J=6.6 Hz)

Example 75 N-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-methylnicotineamide

Yield 0.13 g

White Powder

¹H-NMR (CDCl₃) δ: 8.52 (1H, br s), 7.86 (1H, d, J=7.5 Hz), 7.76 (1H, d,J=7.5 Hz), 7.69 (1H, s), 7.59 (1H, d, J=4.2 Hz), 7.56 (1H, s), 6.92 (1H,d, J=8.7 Hz), 4.58 (2H, d, J=5.1 Hz), 3.91 (3H, s), 3.84 (2H, d, J=6.9Hz), 2.69 (3H, s), 2.23-2.15 (1H, m), 1.05 (6H, d, J=5.1 Hz)

Example 76

Using 0.2 g of{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamineobtained in Reference Example 25, 0.24 g of white powderyN-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-methoxypicolinamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.24-8.19 (2H, m), 7.72 (1H, dd, J=8.4, 1.8 Hz), 7.65(1H, d, J=0.9 Hz), 7.62 (1H, d, J=1.8 Hz), 7.43-7.35 (2H, m), 6.98 (1H,d, J=8.4 Hz), 4.60 (2H, dd, J=5.7, 0.9 Hz), 4.46 (2H, q, J=5.4 Hz), 3.95(3H, s), 3.93 (3H, s)

Using 0.2 g of{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamineobtained in Reference Example 25, compounds of Example 77 to 79 wereobtained in the same manner as in Example 1.

Example 77N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-ethoxypicolinamide

Yield 0.24 g

White Powder

¹H-NMR (CDCl₃) δ: 8.26-8.22 (2H, m), 7.72 (1H, dd, J=8.4, 2.1 Hz), 7.65(1H, s), 7.63 (1H, d, J=1.8 Hz), 7.40-7.32 (2H, m), 6.98 (1H, d, J=8.1Hz), 4.62 (2H, dd, J=5.7, 0.9 Hz), 4.46 (2H, q, J=8.4 Hz), 4.18 (2H, q,J=6.9 Hz), 1.52 (3H, t, J=6.9 Hz)

Example 78N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-methoxybenzamide

Yield 0.18 g

White Powder

¹H-NMR (CDCl₃) δ: 8.42 (1H, br s), 8.23 (1H, dd, J=7.5, 1.8 Hz), 7.73(1H, dd, J=8.4, 2.1 Hz), 7.65-7.60 (2H, m), 7.48-7.42 (1H, m), 7.08 (1H,td, J=8.4, 0.9 Hz), 6.98 (1H, d, J=8.4 Hz), 4.62 (2H, dd, J=5.4, 0.9Hz), 4.46 (2H, q, J=8.4 Hz), 3.98 (3H, s), 3.93 (3H, s)

Example 79N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-methylbenzamide

Yield 0.15 g

White Powder

¹H-NMR (CDCl₃) δ: 7.72 (1H, dd, J=8.4, 2.1 Hz), 7.66 (1H, s), 7.61 (1H,d, J=2.1 Hz), 7.41-7.14 (4H, m), 6.98 (1H, d, J=8.4 Hz), 6.31 (1H, brs), 4.58 (2H, dd, J=5.4, 0.9 Hz), 4.45 (2H, q, J=8.4 Hz), 3.93 (3H, s),2.46 (3H, s)

Using 0.15 g of{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamineobtained Reference Example 25, compounds of Examples 80 to 82 wereobtained in the same manner as in Example 1.

Example 80N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-propoxybenzamide

Yield 0.15 g

White Powder

¹H-NMR (CDCl₃) δ: 8.53 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz), 7.73(1H, dd, J=8.4, 2.1 Hz), 7.65-7.60 (2H, m), 7.45-7.38 (1H, m), 7.09-6.93(3H, m), 4.62 (2H, d, J=5.1 Hz), 4.45 (2H, q, J=8.1 Hz), 4.07 (2H, t,J=6.6 Hz), 3.94 (3H, s), 1.88 (2H, qt, J=7.5, 6.6 Hz), 0.98 (3H, t,J=7.5 Hz)

Example 81N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-isopropoxybenzamide

Yield 0.18 g

White Powder

¹H-NMR (CDCl₃) δ: 8.64 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz), 7.74(1H, dd, J=8.4, 2.1 Hz), 7.65 (1H, d, J=2.1 Hz), 7.63 (1H, s), 7.44-7.37(1H, m), 7.08-6.94 (3H, m), 4.73 (1H, tt, J=6.0 Hz), 4.62 (2H, dd,J=5.1, 0.9 Hz), 4.46 (2H, q, J=8.4 Hz), 3.94 (3H, s), 1.41 (6H, d, J=6.0Hz)

Example 82N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-4-chloro-2-methoxybenzamide

Yield 0.21 g

White Powder

¹H-NMR (CDCl₃) δ: 8.29 (1H, br s), 8.17 (1H, d, J=8.4 Hz), 7.73 (1H, dd,J=8.4, 1.8 Hz), 7.64 (1H, d, J=1.5 Hz), 7.07 (1H, dd, J=8.4, 1.8 Hz),7.00-6.96 (2H, m), 4.60 (2H, dd, J=5.4, 0.9 Hz), 4.46 (2H, q, J=8.4 Hz),3.98 (3H, s), 3.93 (3H, s)

Example 83

Using 0.1 g of{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamineobtained in Reference Example 34, 0.11 g of white powderyN-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.54 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz) 7.64(1H, s), 7.60-7.55 (2H, m), 7.45-7.38 (1H, m), 7.10-7.04 (2H, m), 6.94(1H, d, J=8.1 Hz), 4.62 (2H, dd, J=5.4, 0.9 Hz), 4.48 (2H, q, J=8.4 Hz),4.18 (2H, q, J=6.9 Hz), 3.95 (2H, d, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz),1.35-1.29 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35 (2H, m)

Example 84

Using 0.18 g of{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}methylamineobtained in Reference Example 34, 0.2 g of white powderyN-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-methylpicolinamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.39 (1H, dd, J=4.5, 1.2 Hz) 7.64(1H, s), 7.60-7.55 (3H, m), 7.32-7.26 (1H, m), 7.06-7.03 (1H, m), 4.59(2H, dd, J=5.7, 0.9 Hz), 4.48 (2H, q, J=8.4 Hz), 3.95 (2H, d, J=6.9 Hz),2.76 (3H, s), 1.38-1.28 (1H, m), 0.69-0.62 (2H, m), 0.40-0.35 (2H, m)

Example 85

Using 0.3 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]methylamine obtainedin Reference Example 37, 0.11 g of white powderyN-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-propoxy benzamide wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.51 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz),7.60-7.50 (3H, m), 7.41 (1H, m), 7.06 (1H, m), 7.00-6.90 (2H, m), 4.61(2H, d, J=5.1 Hz), 4.06 (2H, t, J=6.6 Hz), 1.87 (2H, tq, J=7.2, 6.6 Hz),1.49 (6H, t, J=6.9 Hz), 0.96 (3H, t, J=7.2 Hz)

Using 0.3 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]methylamine obtainedin Reference Example 37, compounds of Examples 86 to 91 were obtained inthe same manner as in Example 1.

Example 86 N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamide

Yield 0.11 g

White Powder

¹H-NMR (CDCl₃) δ: 7.75-7.50 (7H, m), 6.91 (1H, d, J=8.4 Hz), 6.32 (1H,br s), 4.59 (2H, d, J=5.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.14 (2H, q,J=6.9 Hz), 1.48 (6H, t, J=6.9 Hz)

Example 87 N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]picolinamide

Yield 0.34 g

White Powder

¹H-NMR (CDCl₃) δ: 8.55 (1H, m), 8.47 (1H, br s), 8.21 (1H, d, J=7.8 Hz),7.85 (1H, m), 7.57 (1H, dd, J=8.4, 1.8 Hz), 7.55 (1H, d, J=1.8 Hz), 7.42(1H, m), 6.91 (1H, d, J=8.4 Hz), 6.32 (1H, br s), 4.63 (2H, d, J=6.0Hz), 4.18 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9Hz), 1.48 (3H, t, J=6.9 Hz)

Example 88 N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide

Yield 0.23 g

White Powder

¹H-NMR (CDCl₃) δ: 8.55 (1H, m), 8.47 (1H, br s), 8.21 (1H, d, J=7.8 Hz),7.85 (1H, m), 7.57 (1H, dd, J=8.4, 1.8 Hz), 7.55 (1H, d, J=1.8 Hz), 7.42(1H, m), 6.91 (1H, d, J=8.4 Hz), 6.32 (1H, br s), 4.63 (2H, d, J=6.0Hz), 4.18 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9Hz), 1.48 (3H, t, J=6.9 Hz)

Example 89 N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-4-ethoxybenzamide

Yield 0.32 g

White Powder

¹H-NMR (CDCl₃) δ: 7.80-7.70 (2H, m), 7.63 (1H, s), 7.60-7.50 (2H, m),6.95-6.85 (3H, m), 6.66 (1H, br s), 4.57 (2H, q, J=6.0 Hz), 4.17 (2H, q,J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 4.06 (2H, q, J=6.9 Hz), 1.48 (3H, t,J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.42 (3H, t, J=6.9 Hz).

Example 90N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-5-methoxy-2-trifluoromethoxybenzamide

Yield 0.34 g

White Powder

¹H-NMR (CDCl₃) δ: 7.95 (1H, br s), 7.73 (1H, d, J=3.0 Hz), 7.70-7.50(3H, m), 6.99 (1H, dd, J=9.0, 3.0 Hz), 6.90-6.80 (2H, m), 4.61 (2H, d,J=6.0 Hz), 4.18 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 3.82 (3H, s),1.48 (3H, t, J=6.9 Hz), 1.46 (3H, t, J=6.9 Hz)

Example 91 N-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-ethoxybenzamide

Yield 0.12 g

White Powder

¹H-NMR (CDCl₃) δ: 7.57 (1H, dd, J=8.1, 2.1 Hz), 7.53 (1H, d, J=2.1 Hz),7.35-7.25 (3H, m), 7.01 (1H, m), 6.92 (1H, d, J=8.1 Hz), 6.68 (1H, brs), 4.58 (2H, d, J=5.4 Hz), 4.18 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9Hz), 4.07 (2H, q, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9Hz), 1.42 (3H, t, J=6.9 Hz)

Example 92

Using 0.3 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine obtainedin Reference Example 40, 0.27 g of white powderyN-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy benzamide wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.24 (1H, dd, J=8.1, 1.8 Hz),7.65-7.60 (2H, m), 7.55 (1H, d, J=1.5 Hz), 7.42 (1H, m), 7.07 (1H, m),6.95-6.90 (2H, m), 4.63 (2H, d, J=5.1 Hz), 4.18 (2H, q, J=6.9 Hz), 3.98(3H, s), 3.97 (3H, s), 1.26 (3H, t, J=6.9 Hz)

Example 93

Using 0.25 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine obtainedin Reference Example 40, 0.23 g of white powderyN-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-2-ethyl benzamide wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 7.66 (1H, s), 7.60 (1H, dd, J=8.4, 1.8 Hz), 7.52 (1H,d, J=1.8 Hz), 7.40-7.20 (4H, m), 6.93 (1H, d, J=8.4 Hz), 6.34 (1H, brs), 4.58 (2H, d, J=5.4 Hz), 3.96 (3H, s), 3.94 (3H, s), 2.82 (2H, q,J=7.5 Hz), 1.20 (3H, t, J=7.5 Hz)

Example 94

Using 0.2 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine obtainedin Reference Example 40, 0.16 g of white powderyN-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-3-methyl picolinamide wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, m), 7.65-7.55 (4H, m), 7.30(1H, m), 6.92 (1H, d, J=8.4 Hz), 4.59 (2H, d, J=6.0 Hz), 3.97 (3H, s),3.93 (3H, s), 2.76 (3H, s), 1.58 (3H, s)

Example 95

Using 0.2 g of [2-(3,4-dimethoxyphenyl)oxazol-4-yl]methylamine obtainedin Reference Example 40, 0.12 g of white powderyN-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-3-methoxy picolinamide wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.21 (1H, br s), 8.20 (1H, dd, J=3.9, 1.8 Hz), 7.65(1H, s), 7.61 (1H, dd, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz), 7.45-7.30(2H, m), 6.92 (1H, d, J=8.4 Hz), 4.61 (2H, d, J=6.0 Hz), 3.97 (3H, s),3.96 (3H, s), 3.93 (3H, s)

Example 96

0.13 g of[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]methylamine obtainedin Reference Example 46 was suspended in 10 ml of acetone. Then 0.14 gof 1-hydroxybenzotriazole and 0.19 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.14 gof 3-methyl picolinate were added to the obtained suspension and themixture was refluxed for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and water was added to the residue.Ethyl acetate extraction was performed. The organic layer was washedtwice with water, and concentrated. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=1:1), yielding 0.16 gof white powderyN-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.40 (1H, d, J=3.9 Hz), 7.74-7.58(4H, m), 7.47-7.23 (7H, m), 6.62 (1H, t, J=74.7 Hz), 5.21 (2H, s), 4.60(2H, d, J=5.7 Hz), 2.76 (3H, s)

Example 97

0.16 g ofN-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamideobtained in Example 96 was dissolved in 5 ml of ethanol, 20 mg of 10%palladium carbon powder was added thereto, and the mixture was stirredat room temperature for 30 minutes under a hydrogen atmosphere. Thecatalyst was filtered off, and the filtrate was concentrated to obtain0.12 g of white powderyN-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.60-8.54 (1H, m), 8.39 (1H, d, J=3.3 Hz), 7.69-7.55(4H, m), 7.37-7.28 (1H, m), 7.18 (1H, d, J=8.4 Hz), 6.59 (1H, t, J=73.2Hz), 5.79 (1H, br s), 4.59 (2H, dd, J=6.0, 0.9 Hz), 2.76 (3H, s)

Example 98

0.12 g ofN-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamideobtained in Example 97 and 0.15 ml of 1,8-diazabicyclo[5,4,0]undec-7-enewere dissolved in 4 ml of ethanol. 0.15 ml of (bromomethyl)cyclopropanewas added thereto and refluxed with heating for 3 hours. The solvent wasdistilled off, and water was added to the residue. Ethyl acetateextraction was performed. The organic layer was washed twice with water,and concentrated. The residue was purified by silica gel columnchoromatography (n-hexane:ethyl acetate=1:1). The obtained crudecrystals were recrystallized using an ethanol-n-hexane mixture, and 60mg of white powderyN-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained.

¹H-NMR (CDCl₃) δ: 8.59-8.54 (1H, m), 8.39 (1H, dd, J=4.5, 1.2 Hz), 7.67(1H, s), 7.63-7.56 (3H, m), 7.37-7.28 (1H, m), 7.22 (1H, d, J=8.1 Hz),6.69 (1H, t, J=75.0 Hz), 4.59 (2H, dd, J=5.7, 0.9 Hz), 3.98 (2H, d,J=6.9 Hz), 2.76 (3H, s), 1.35-1.20 (1H, m), 0.70-0.63 (2H, m), 0.41-0.35(2H, m)

Example 99

Using 0.2 g of[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamineobtained in Reference Example 13, 0.11 g of white powderyN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoquinoline-1-carboxamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 9.60 (1H, m), 8.67 (1H, br s), 8.47 (1H, d, J=2.4 Hz),7.90-7.80 (2H, m), 7.75-7.65 (3H, m), 7.61 (1H, dd, J=8.4, 1.8 Hz), 7.53(1H, d, J=1.8 Hz), 6.92 (1H, d, J=8.4 Hz), 4.68 (2H, d, J=6.0 Hz), 3.94(2H, d, J=7.5 Hz), 3.92 (3H, s), 1.39 (1H, m), 0.70-0.60 (2H, m),0.40-0.35 (2H, m)

Example 100

4.42 g of sodium hydroxide was suspended in 160 ml of dimethoxyethane.The suspension was stirred with ice cooling while 16 g of3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methyl propionate obtainedin Reference Example 48 and 39.23 g of 2-ethoxyperbenzoic acid wereseparately added, and then heating and refluxing were conducted for 7hours. After cooling with ice, saturated ammonium chloride solution wasadded to the mixture and stirred for 30 minutes. Water was then addedthereto, and ethyl acetate extraction was performed, followed by dryingover anhydrous magnesium sulfate, and the solvent was then distilledoff. The residue was subjected to silica gel column purification(n-hexane:ethyl acetate=3:1), and 13.4 g of yellow oily substance,methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-ethoxyphenyl)-3-oxopropionatewas obtained.

¹H-NMR (CDCl₃) δ: 7.71 (1H, d, J=7.8 Hz), 7.57-7.54 (3H, m), 7.48-7.28(6H, m), 6.99-6.90 (3H, m), 5.16 (2H, s), 4.98 (1H, t, J=6.9 Hz), 4.14(2H, q, J=6.9 Hz), 3.91 (3H, s), 3.70 (3H, s), 3.27-3.19 (2H, m), 1.45(3H, t, J=6.9 Hz)

Example 101

A 13.4 g quantity of methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-ethoxyphenyl)-3-oxopropionateobtained in Example 100 was suspended in 67 ml of ethanol, 67 ml of 47%hydrobromic acid was added thereto, and the suspension was heated andrefluxed overnight. After standing to cool, the crystals generated werecollected by filtration, washed with water and diisopropyl ether, anddried, thereby yielding 8.1 g of white powdery1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.

¹H-NMR (CDCl₃) δ: 8.30 (1H, d, J=8.7 Hz), 7.84 (1H, d, J=1.8 Hz),7.83-7.71 (2H, m), 7.45 (1H, t, J=8.4 Hz), 7.06 (1H, d, J=8.7 Hz),6.99-6.93 (2H, m), 4.17 (2H, q, J=6.9 Hz), 4.00 (3H, s), 3.67 (2H, t,J=6.6 Hz), 3.35 (2H, t, J=6.6 Hz), 1.55 (3H, t, J=6.9 Hz)

Example 102

A 8.1 g quantity of1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-oneobtained in Example 101 was suspended in 220 ml of ethanol, 10 g of1,8-diazabicyclo[5,4,0]undec-7-ene and 5.96 g of(bromomethyl)cyclopropane were added thereto, and stirring was conductedfor 5 hours while heating and refluxing. After distilling off ethanolunder reduced pressure, water was added, ethyl acetate extraction wasperformed, followed by drying over anhydrous magnesium sulfate anddistilling the solvent off. The residue was subjected to silica gelcolumn purification (n-hexane:ethyl acetate=4:1), and the obtained crudecrystals were recrystallized using ethanol, thereby yielding 4.4 g ofwhite powdery3-[2-(3-cycropropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.56 (1H, dd, J=8.4, 2.1Hz), 7.50 (1H, s), 7.45-7.39 (2H, m), 7.00-6.89 (3H, m), 4.13 (2H, q,J=7.2 Hz), 3.93-3.91 (5H, m), 3.41 (2H, t, J=6.6 Hz), 2.99 (2H, t, J=6.6Hz), 1.51 (3H, t, J=7.2 Hz), 1.47 (1H, m), 0.67-0.64 (2H, m), 0.40-0.36(2H, m)

Example 103

A 0.3 g quantity of1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-oneobtained in Example 101 was suspended in 10 ml of ethanol, 0.37 g of1,8-diazabicyclo[5,4,0]undec-7-ene and 0.26 g of ethyl iodide were addedthereto, and the suspension was stirred for 4 hours while heating andrefluxing. After distilling off ethanol under reduced pressure, waterwas added, ethyl acetate extraction was performed, followed by dryingover anhydrous magnesium sulfate and distilling the solvent off. Theresidue was subjected to silica gel column purification (n-hexane:ethylacetate=3:1), thereby yielding 0.15 g of white powdery3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H -NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.56 (1H, dd, J=8.4,1.8 Hz), 7.52-7.40 (2H, m), 6.99-6.89 (3H, m), 4.21-4.09 (4H, m), 3.91(3H, s), 3.42 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz), 1.51-1.45 (6H,m)

Example 104

A 0.3 g quantity of1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-oneobtained in Example 101 was suspended in 10 ml of ethanol, 0.37 g of1,8-diazabicyclo[5,4,0]undec-7-ene and 0.14 ml of allyl bromide wereadded thereto, and stirring was conducted for 3 hours while heating andrefluxing. After distilling off ethanol under reduced pressure, waterwas added, ethyl acetate extraction was performed, followed by dryingover anhydrous magnesium sulfate and distilling the solvent off. Theresidue was subjected to silica gel column purification (n-hexane:ethylacetate=3:1), thereby yielding 0.2 g of white powdery3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.58 (1H, dd, J=8.4, 1.8Hz), 7.52 (1H, d, J=1.8 Hz), 7.45-7.40 (2H, m), 7.00-6.90 (3H, m),6.18-6.05 (1H, m), 5.47-5.29 (2H, m), 4.67 (2H, d, J=5.1 Hz), 4.13 (2H,q, J=6.9 Hz), 3.92 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2Hz), 1.47 (3H, t, J=6.9 Hz).

Using 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101, compounds ofExamples 105 to 110 were obtained in the same manner as in Examples 102.

Example 1053-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.57-7.51 (2H, m),7.45-7.39 (2H, m), 6.99-6.88 (3H, m), 4.88 (1H, br s), 4.12 (2H, q,J=6.9 Hz), 3.88 (3H, s), 3.42 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz),2.04-1.87 (6H, m), 1.65-1.60 (2H, m), 1.47 (3H, t, J=6.9 Hz)

Example 1063-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8Hz), 7.50 (1H, d, J=2.1 Hz), 7.45-7.40 (2H, m), 4.13 (2H, q, J=6.9 Hz),3.90 (3H, s), 3.84 (2H, d, J=6.9 Hz), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H,t, J=7.2 Hz), 2.23-2.14 (1H, m), 1.48 (3H, t, J=6.9 Hz), 1.05 (6H, d,J=6.9 Hz)

Example 1071-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-propoxyphenyl)oxazol-4-yl]propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.56 (1H, dd, J=8.1, 1.8Hz), 7.52 (1H, s), 7.45-7.40 (2H, m), 7.00-6.89 (3H, m), 4.13 (2H, q,J=6.9 Hz), 4.05 (2H, t, J=6.9 Hz), 3.90 (3H, s), 3.42 (2H, t, J=7.5 Hz),3.00 (2H, t, J=7.5 Hz), 1.95-1.84 (2H, m), 1.47 (3H, t, J=6.9 Hz), 1.05(3H, t, J=6.9 Hz)

Example 1083-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.57 (1H, dd, J=8.4, 1.8Hz), 7.52 (1H, s), 7.45-7.40 (2H, m), 6.97-6.89 (3H, m), 6.00-5.90 (1H,m), 5.22-5.10 (2H, m), 4.17-4.11 (4H, m), 3.90 (3H, s), 3.42 (2H, t,J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.67-2.62 (2H, m), 1.47 (3H, t, J=6.9Hz)

Example 1093-[2-(3-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.57 (1H, dd, J=8.4, 1.8Hz), 7.53 (1H, d, J=2.1 Hz), 7.45-7.39 (2H, m), 7.00-6.89 (3H, m),4.16-4.07 (4H, m), 3.98 (3H, s), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t,J=7.2 Hz), 1.90-1.86 (2H, m), 1.57-1.42 (5H, m), 0.99 (3H, t, J=7.2 Hz)

Example 1101-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-(2-propenyloxy)phenyl)oxazol-4-yl]propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.66-7.63 (2H, m),7.46-7.39 (2H, m), 7.00-6.92 (3H, m), 4.83 (2H, d, J=2.1 Hz), 4.13 (2H,q, J=6.9 Hz), 3.92 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2Hz), 2.52 (1H, t, J=2.1 Hz), 1.47 (3H, t, J=6.9 Hz)

Example 111

A 5.0 g quantity of1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-oneobtained in Example 101 was dissolved in 50 ml of dimethylformamide,3.35 g of 2-bromopropane and 5.63 g of potassium carbonate were addedthereto, and stirring was conducted overnight at room temperature. Waterwas added to the obtained mixture, ethyl acetate extraction wasperformed, followed by drying over anhydrous magnesium sulfate anddistilling the solvent off. The residue was subjected to silica gelcolumn purification (n-hexane:ethyl acetate=4:1), and the obtained crudecrystals were recrystallized using ethanol, thereby yielding 2.99 g ofwhite powdery1-(2-ethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.59-7.54 (2H, m),7.45-7.39 (2H, m), 7.00-6.89 (3H, m), 4.68-4.60 (1H, m), 4.13 (2H, q,J=6.9 Hz), 3.89 (3H, s), 3.42 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz),1.47 (3H, t, J=6.9 Hz), 1.39 (6H, d, J=6.3 Hz)

Using 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propane-1-one obtained in Example 101, compounds ofExamples 112 to 122 were obtained in the same manner as in Example 111.

Example 1121-(2-ethoxyphenyl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propan-1-one

¹H-NMR (CDCl₃) δ: 7.72-7.68 (2H, m), 7.60 (1H, d, J=1.8 Hz), 7.45-7.39(2H, m), 7.00-6.92 (3H, m), 4.44 (2H, q, J=8.4 Hz), 4.13 (2H, q, J=6.6Hz), 3.90 (3H, s), 3.42 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz), 1.48(3H, t, J=6.6 Hz)

Example 1133-[2-(3-cyclohexylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8Hz), 7.50 (1H, d, J=1.8 Hz), 7.45-7.40 (2H, m), 7.00-6.88 (3H, m), 4.14(2H, q, J=6.9 Hz), 3.90 (3H, s), 3.86 (2H, d, J=6.0 Hz), 3.42 (2H, t,J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.00-1.86 (3H, m), 1.79-1.63 (3H, m),1.45 (3H, t, J=6.9 Hz), 1.40-1.22 (2H, m), 1.10-1.02 (2H, m)

Example 1143-[2-(3-cyclopentylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8Hz), 7.50 (1H, d, J=1.8 Hz), 7.45-7.40 (2H, m), 7.00-6.88 (3H, m), 4.14(2H, q, J=6.9 Hz), 3.95 (2H, d, J=7.2 Hz), 3.90 (3H, s), 3.42 (2H, t,J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.48-2.44 (1H, m), 2.04-1.86 (2H, m),1.63-1.50 (4H, m), 1.45 (3H, s), 1.39-1.35 (2H, m)

Example 115 1-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-(4-pentenyloxy)phenyl)oxazol-4-yl]propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 2.1 Hz), 7.56 (1H, dd, J=8.1, 2.1Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.39 (2H, m), 7.00-6.89 (3H, m),5.87-5.81 (1H, m), 5.10-4.99 (2H, m), 4.17-4.08 (4H, m), 3.91 (3H, s),3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.27-2.22 (2H, m),2.04-1.95 (2H, m), 1.47 (3H, t, J=7.2 Hz)

Example 1163-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 2.1 Hz), 7.56 (1H, dd, J=8.1, 2.1Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.39 (2H, m), 7.00-6.80 (3H, m), 4.13(2H, q, J=7.2 Hz), 4.07 (2H, d, J=7.2 Hz), 3.90 (3H, s), 3.42 (2H, t,J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.96-2.85 (1H, m), 2.20-2.14 (2H, m),1.91-1.80 (2H, m), 1.45 (3H, t, J=7.2 Hz)

Example 1171-(2-ethoxyphenyl)-3-{2-[4-methoxy-3-(3-methyl-2-butenyloxy)phenyl]oxazol-4-yl}propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.57 (1H, dd, J=8.1, 1.8Hz), 7.51 (1H, d, J=1.8 Hz), 7.00-6.89 (3H, m), 5.55 (1H, t, J=6.6 Hz),4.64 (2H, d, J=6.6 Hz), 4.13 (2H, q, J=6.9 Hz), 3.91 (3H, s), 3.42 (2H,t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.77 (6H, d, J=6.6 Hz), 1.45 (3H,t, J=6.9 Hz)

Example 1183-{2-[3-(2-cyclohexenyloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.60-7.57 (2H, m),7.42-7.39 (2H, m), 7.00-6.89 (3H, m), 6.00-5.92 (2H, m), 4.88 (1H, brs), 4.15 (2H, q, J=7.2 Hz), 3.89 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99(2H, t, J=7.2 Hz), 2.04-1.80 (4H, m), 1.72-1.53 (2H, m), 1.45 (3H, t,J=7.2 Hz)

Example 1191-(2-ethoxyphenyl)-3-[2-(4-methoxy-3-phenethyloxyphenyl)oxazol-4-yl]propan-1-one

¹H-NMR (CDCl₃) δ: 7.69 (1H, dd, J=7.8, 1.8 Hz), 7.59 (1H, dd, J=8.4, 1.8Hz), 7.56 (1H, d, J=1.8 Hz), 7.51-6.98 (7H, m), 6.95-6.90 (3H, m), 4.27(2H, t, J=7.2 Hz), 4.11 (2H, q, J=6.9 Hz), 3.91 (3H, s), 3.41 (2H, t,J=7.2 Hz), 3.20 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.54 (3H, t,J=6.9 Hz)

Example 1201-(2-ethoxyphenyl)-3-{2-[4-methoxy-3-(3-phenylpropoxy)phenyl]oxazol-4-yl}propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.58 (1H, dd, J=8.4, 1.8Hz), 7.56 (1H, d, J=1.8 Hz), 7.49-7.39 (2H, m), 7.30-7.15 (5H, m),6.99-6.90 (3H, m), 4.16-4.08 (4H, m), 3.92 (3H, s), 3.42 (2H, t, J=7.2Hz), 2.98 (2H, t, J=7.2 Hz), 2.84 (2H, t, J=8.1 Hz), 2.24-2.15 (2H, m),1.46 (3H, t, J=6.9 Hz)

Example 1213-{2-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.57-7.55 (2H, m),7.43-7.39 (2H, m), 7.00-6.89 (3H, m), 4.19-4.10 (4H, m), 3.91 (3H, s),3.42 (2H, t, J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz), 1.81-1.74 (2H, m), 1.48(3H, t, J=6.9 Hz), 0.88-0.83 (1H, m), 0.52-0.47 (2H, m), 0.16-0.12 (2H,m)

Example 1223-{2-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.56 (1H, dd, J=8.4, 1.8Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.39 (2H, m), 7.00-6.89 (3H, m),4.17-4.07 (4H, m), 3.90 (3H, s), 3.42 (2H, t, J=6.9 Hz), 3.00 (2H, t,J=6.9 Hz), 2.00-1.81 (5H, m), 1.66-1.62 (4H, m), 1.45 (3H, t, J=6.9 Hz),1.28-1.15 (2H, m)

Example 123

A 1.0 g quantity of methyl3-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propionateobtained in Reference Example 49 and 0.54 g of methyl3-methoxypicolinate were added to 5 ml of dimethylformamide, and themixture was stirred with ice cooling for 10 minutes. A 0.83 g of sodiumt-pentoxide was added to the obtained mixture, which was then stirredwith ice cooling for an hour, followed by further stirring at roomtemperature for 1 hour. The reaction mixture was stirred with icecooling, saturated ammonium chloride solution was added thereto, andfurther stirred for 30 minutes. Water was added to the mixture, ethylacetate extraction was performed, followed by drying over anhydrousmagnesium sulfate and distilling the solvent off. A 5.0 ml quantity ofdimethylsulfoxide, 84 mg of lithium chloride and 41 μl of purified waterwere added to the residue, and the mixture was stirred with heating at110° C. overnight. After standing to cool, water was added to theobtained mixture, ethyl acetate extraction was performed, followed bydrying over anhydrous magnesium sulfate and distilling the solvent off.The obtained residue was subjected to silica gel column purification(n-hexane:ethyl acetate=4:1), and the obtained crude crystals wererecrystallized from a mixture of ethyl acetate and diisopropyl ether,thereby yielding 0.11 g white powdery 3-{2-[3-cyclopropylmethoxy-4-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methoxypyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.24 (1H, d, J=4.2 Hz), 7.55-7.47 (2H, m), 7.43 (1H,s), 7.40-7.35 (2H, m), 7.03 (1H, d, J=8.4 Hz), 4.46 (2H, q, J=7.2 Hz),3.94 (2H, d, J=6.6 Hz), 3.90 (3H, s), 3.51 (2H, d, J=7.2 Hz), 3.01 (2H,d, J=7.2 Hz), 1.31-1.26 (1H, m), 0.68-0.62 (2H, m), 0.39-0.34 (2H, m)

Example 124

A 2 g quantity of methyl 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate obtained in Reference Example 48 and 1.1 gof methyl 3-methoxypicolinate were dissolved in 10 ml ofdimethylformamide, and while stirring the solution with ice cooling 1.81g of sodium t-pentoxide was added thereto and stirred for 30 minutes.The mixture was further stirred for 5 hours at room temperature, ice wasadded to the reaction mixture, followed by addition of saturated aqueousammonium chloride solution, and the mixture was further stirred. Afterstirring the reaction mixture for 30 minutes, water was added theretoand ethyl acetate extraction was performed. The organic layer was washedtwice with water, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1), thereby yielding 1.55 g of white amorphous methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-methoxypyridin-2-yl)-3-oxopropionate.

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=4.5, 1.8 Hz), 7.57-7.28 (10H, m), 6.91(1H, d, J=9.0 Hz), 5.18-5.13 (3H, m), 3.91-3.90 (6H, m), 3.64 (3H, s),3.36-3.18 (2H, m)

Example 125

A 1.5 g quantity of methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-methoxypyridin-2-yl)-3-oxopropionateobtained in Example 124 was dissolved in 22.5 ml of ethanol, 7.5 ml of47% hydrobromic acid was added thereto, and the mixture was stirred withheating at 80° C. for 7.5 hours. While stirring with ice cooling, thereaction mixture was neutralized with a 5N sodium hydroxide solution,and ethyl acetate extraction was performed. The organic layer was washedtwice with water, and concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(dichloromethane:methanol=20:1), thereby yielding 0.65 g of pale yellowoily substance,3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=7.2, 1.5 Hz), 7.55-7.27 (5H, m), 6.88(1H, d, J=8.7 Hz), 5.72 (1H, s), 3.92-3.89 (6H, m), 3.51 (2H, t, J=7.5Hz), 3.03 (2H, t, J=7.5 Hz)

Example 126

Using 0.24 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridine-2-yl)propan-1-oneobtained in Example 125, 0.11 g of white powdery3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2-yl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=4.2, 1.2 Hz), 7.59-7.32 (5H, m), 6.91(1H, d, J=8.4 Hz), 3.94-3.90 (8H, m), 3.51 (2H, t, J=7.2 Hz), 3.01 (2H,t, J=7.2 Hz), 1.40-1.30 (1H, m), 0.69-0.62 (2H, m), 0.41-0.35 (2H, m)

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2-yl)propan-1-oneobtained in Example 125, compounds of Examples 127 and 128 were obtainedin the same manner as in Example 102.

Example 127 3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=4.2, 1.5 Hz), 7.58-7.30 (5H, m), 6.91(1H, d, J=8.4 Hz), 3.92-3.90 (6H, m), 3.84 (2H, d, J=6.9 Hz), 3.52 (2H,t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.20 (1H, q, J=6.9 Hz), 1.06 (6H,d, J=6.9 Hz)

Example 1283-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methoxypyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=4.5, 1.5 Hz), 7.60-7.30 (5H, m), 6.90(1H, d, J=8.7 Hz), 4.90-4.85 (1H, m), 3.90-3.88 (6H, m), 3.51 (2H, d,J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz), 2.00-1.81 (6H, m), 1.64-1.60 (2H, m)

Example 129

Using 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-3-(3-methoxypyridin-2-yl)propan-1-oneobtained in Example 125, 44 mg of white powdery1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propan-1-onewas obtained in the same manner as in Example 111.

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=4.2, 1.2 Hz), 7.70 (1H, dd, J=8.4, 1.8Hz), 7.60 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.47-7.32 (2H, m),6.96 (1H, d, J=8.4 Hz), 4.45 (2H, q, J=8.4 Hz), 3.95-3.88 (6H, m), 3.52(2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz)

Example 130

A 2 g quantity of methyl 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate obtained in Reference Example 48 and 1 gof methyl 3-ethoxypicolinate were dissolved in 10 ml ofdimethylformamide, and while stirring the solution with ice cooling 1.81g of sodium t-pentoxide was added thereto and stirred for 30 minutes.The mixture was further stirred for 4 hours at room temperature, and icewas added to the reaction mixture, followed by addition of saturatedaqueous ammonium chloride solution for further stirring. After stirringthe reaction mixture for 30 minutes, water was added thereto and ethylacetate extraction was performed. The organic layer was washed twicewith water, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1), thereby yielding 1.5 g of colorless oily substance methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-ethoxypyridin-2-yl)-3-oxopropionate.

¹H-NMR (CDCl₃) δ: 8.22 (1H, dd, J=4.2, 1.2 Hz), 7.57-7.27 (10H, m), 6.91(1H, d, J=9.0 Hz), 5.18-5.12 (3H, m), 4.12 (2H, q, J=6.9 Hz), 3.92 (3H,s), 3.65 (3H, s), 3.30-3.23 (2H, m), 1.46 (3H, t, J=6.9 Hz)

Example 131

Using 1.5 g of methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-ethoxypyridin-2-yl)-3-oxopropionateobtained in Example 130, 0.7 g of pale yellow oily substance,1-(3-ethoxypyridin-2-yl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one,was obtained in the same manner as in Example 125.

¹H-NMR (CDCl₃) δ: 8.23 (1H, dd, J=4.2, 1.2 Hz), 7.55-7.49 (2H, m), 7.45(1H, s), 7.42-7.28 (2H, m), 6.88 (1H, d, J=8.7 Hz), 5.70 (1H, s), 4.11(2H, q, J=6.9 Hz), 3.49 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=6.9 Hz), 1.46(3H, t, J=6.9 Hz)

Example 132

Using 0.2 g of1-(3-ethoxypyridin-2-yl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-oneobtained in Example 131, 0.2 g of pale yellow oily substance,3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-ethoxypyridin-2-yl)propan-1-one,was obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 8.23 (1H, dd, J=4.5, 1.5 Hz), 7.57-7.45 (2H, m), 7.44(1H, d, J=0.9 Hz), 7.38-7.28 (2H, m), 6.89 (1H, d, J=8.7 Hz), 4.89-4.87(1H, m), 4.12 (2H, q, J=6.9 Hz), 3.94-3.91 (5H, m), 3.88 (3H, s), 3.49(2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.01-1.81 (6H, m), 1.65-1.58(2H, m), 1.47 (3H, t, J=6.9 Hz)

Using 1-(3-ethoxypyridin-2-yl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 131, compounds ofExamples 133 and 134 were obtained in the same manner as in Example 102.

Example 1333-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-ethoxypyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.23 (1H, dd, J=4.2, 1.5 Hz), 7.57 (1H, dd, J=8.4, 1.8Hz), 7.50 (1H, d, J=1.8 Hz), 7.45 (1H, d, J=1.8 Hz), 7.38-7.28 (2H, m),6.91 (1H, d, J=8.4 Hz), 4.12 (2H, q, J=6.9 Hz), 3.94-3.91 (5H, m), 3.49(2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz), 1.46 (3H, t, J=6.9 Hz),1.42-1.32 (1H, m), 0.69-0.62 (2H, m), 0.40-0.35 (2H, m)

Example 1341-(3-ethoxypyridin-2-yl)-3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one

¹H-NMR (CDCl₃) δ: 8.23 (1H, dd, J=4.5, 1.5 Hz), 7.56 (1H, dd, J=8.4, 2.1Hz), 7.50 (1H, d, J=2.1 Hz), 7.45 (1H, s), 7.38-7.28 (2H, m), 6.90 (1H,d, J=8.4 Hz), 4.12 (2H, q, J=6.9 Hz), 3.90 (3H, s), 3.85 (2H, d, J=6.6Hz), 3.50 (2H, t, J=6.9 Hz), 3.02 (2H, t, J=6.9 Hz), 2.19 (2H, qt, J=6.6Hz), 1.47 (3H, t, J=6.9 Hz), 1.05 (6H, d, J=6.6 Hz)

Example 135

A 5 g quantity of methyl 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate obtained in Reference Example 48 and 3.2 gof methyl 3-methylpicolinate were dissolved in 150 ml ofdimethoxyethane. While stirring the solution with ice cooling 1.2 g ofsodium hydride was added thereto and further stirred. The reactionmixture was heated and refluxed for 4 hours. At the completion of thereaction, a saturated aqueous ammonium chloride solution was added tothe mixture while stirring with ice cooling, and the mixture was furtherstirred. After stirring the reaction mixture for 30 minutes, water wasadded thereto and ethyl acetate extraction was performed. The organiclayer was washed twice with water, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), thereby yielding 5.5 g ofcolorless oily substance methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionate.

¹H-NMR (CDCl₃) δ: 8.49 (1H, dd, J=4.8, 1.2 Hz), 7.59-7.28 (10H, m), 6.91(1H, d, J=9.0 Hz), 5.23-5.16 (3H, m), 3.91 (3H, s), 3.65 (3H, s),3.37-3.18 (2H, m) 2.59 (3H, s)

Example 136

A 5.5 g quantity of methyl 2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionateobtained in Example 135 was dissolved in 20 ml of ethanol, 80 ml of a 5Naqueous hydrochloric acid solution was added thereto, and the mixturewas stirred with heating at 80° C. for 1.5 hours. While stirring withice cooling, the reaction mixture was neutralized with 5 N aqueoussodium hydroxide solution, and ethyl acetate extraction was performed.The organic layer was washed twice with water, concentrated underreduced pressure, and the obtained crude crystals were recrystallizedwith a mixture of 20 ml of ethanol and 40 ml of n-hexane, therebyyielding 1.92 g of pale yellow powdery 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.49 (1H, dd, J=4.5, 1.2 Hz), 7.60-7.51 (3H, m), 7.44(1H, d, J=0.9 Hz), 7.41-7.29 (1H, m), 6.89 (1H, dd, J=7.8, 1.2 Hz), 5.68(1H, s), 3.93 (3H, s), 3.58 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),2.57 (3H, s)

Example 137

A 0.3 g quantity of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136 and 0.4 ml of 1,8-diazabicyclo[5,4,0]undec-7-enewere dissolved in 5 ml of ethanol, 0.24 g of (bromomethyl)cyclopropanewas added thereto, and the mixture was heated and refluxed for 4.5hours. After standing to cool, water was added to the reaction mixture,and ethyl acetate extraction was performed. The extract was washed twicewith water, the organic layer was then concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.2 g ofwhite powdery3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.60-7.54 (2H, m), 7.49(1H, d, J=1.8 Hz), 7.45 (1H, s), 7.34-7.29 (1H, m), 6.91 (1H, d, J=8.7Hz), 3.94-3.91 (5H, m), 3.60 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),2.57 (3H, s), 1.40-1.32 (1H, m), 0.69-0.62 (2H, m), 0.41-0.35 (2H, m)

Example 138

A 0.23 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained inExample 136 and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene weredissolved in 5 ml of ethanol, 0.21 g of ethyl iodide was added thereto,and the mixture was heated and refluxed for 4 hours. After standing tocool, water was added to the reaction mixture, and ethyl acetateextraction was performed. The extract was washed twice with water, theorganic layer was then concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), thereby yielding 0.17 g of white powdery3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.24 (1H, d, J=4.2 Hz), 7.58-7.55 (2H, m), 7.51 (1H,d, J=2.1 Hz), 7.45 (1H, s), 6.90 (1H, d, J=8.4 Hz), 4.19 (2H, q, J=7.2Hz), 3.91 (3H, s), 3.59 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.57(3H, s), 1.49 (3H, t, J=7.2 Hz)

Example 139

A 0.3 g quantity of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136 and 0.4 ml of 1,8-diazabicyclo[5,4,0]undec-7-enewere dissolved in 5 ml of ethanol, 0.23 g of 2-bromopropane was addedthereto, and the mixture was heated and refluxed for 4.5 hours. Afterstanding to cool, water was added to the reaction mixture, and ethylacetate extraction was performed. The extract was washed twice withwater, the organic layer was then concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.16 g ofwhite powdery3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.59-7.53 (3H, m), 7.45(1H, s), 7.34-7.31 (1H, m), 6.91 (1H, d, J=8.7 Hz), 4.65 (1H, sept.,J=6.0 Hz), 3.89 (3H, s), 3.59 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),2.62 (3H, s), 1.39 (6H, d, J=6.0 Hz)

Example 140

A 0.3 g quantity of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136 and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-enewere dissolved in 6 ml of ethanol, 0.22 g of allyl bromide was addedthereto, and the mixture was heated and refluxed for 4 hours. Afterstanding to cool, water was added to the reaction mixture, and ethylacetate extraction was performed. The extract was washed twice withwater, the organic layer was then concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.18 g ofwhite powdery3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.51-8.48 (1H, m), 7.60-7.56 (2H, m), 7.52 (1H, d,J=2.1 Hz), 7.45 (1H, s), 7.34-7.29 (1H, m), 6.92 (1H, d, J=8.7 Hz),6.16-6.05 (1H, m), 5.48-5.28 (2H, m), 4.69-4.66 (2H, m), 3.92 (3H, s),3.60 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.57 (3H, s)

Example 141

A 0.15 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained inExample 136 and 0.15 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene weredissolved in 5 ml of ethanol, 0.13 g of (bromomethyl)cyclobutane wasadded thereto, and the mixture was heated and refluxed overnight. Afterstanding to cool, water was added to the reaction mixture, and ethylacetate extraction was performed. The extract was washed twice withwater, the organic layer was then concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), thereby yielding 90 mg ofwhite powdery3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.60-7.51 (3H, m), 7.45(1H, d, J=2.1 Hz), 7.34-7.29 (1H, m), 6.89 (1H, d, J=8.7 Hz), 4.07 (2H,d, J=6.9 Hz), 3.89 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5Hz), 2.89-2.83 (1H, m), 2.57 (3H, s), 2.22-2.13 (2H, m), 2.00-1.84 (4H,m)

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136, compounds of Examples 142 to 154 were obtainedin the same manner as in Example 137.

Example 142 3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.60-7.53 (2H, m), 7.50(1H, d, J=1.8 Hz), 7.45 (1H, s), 7.34-7.28 (1H, m), 6.90 (1H, d, J=8.4Hz), 3.90 (3H, s), 3.84 (2H, d, J=6.9 Hz), 3.60 (2H, t, J=7.8 Hz), 3.01(2H, t, J=7.8 Hz), 2.57 (3H, s), 2.20 (1H, qt, J=6.9 Hz), 1.05 (6H, d,J=6.9 Hz)

Example 1433-[2-(4-methoxy-3-propoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.59-7.54 (2H, m), 7.51(1H, d, J=1.8 Hz), 7.50 (1H, s), 7.34-7.29 (1H, m), 6.90 (1H, d, J=8.4Hz), 4.05 (2H, t, J=6.9 Hz), 3.91 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01(2H, t, J=7.5 Hz), 2.57 (3H, s), 1.90 (2H, qt, J=6.9 Hz), 1.24 (3H, t,J=6.9 Hz)

Example 1443-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridine-2-yl)propane-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.59-7.50 (3H, m), 7.44(1H, d, J=1.2 Hz), 7.34-7.31 (1H, m), 6.89 (1H, d, J=8.4 Hz), 4.90-4.84(1H, m), 3.88 (3H, s), 3.59 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),2.57 (3H, s), 2.03-1.80 (6H, m), 1.64-1.58 (2H, m)

Example 1453-[2-(4-methoxy-3-(2-propenyloxy)phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.67-7.63 (2H, m), 7.58 (1H,d, J=8.1 Hz), 7.46 (1H, s), 7.34-7.30 (1H, m), 6.93 (1H, dd, J=6.6, 2.4Hz), 4.82 (2H, d, J=2.4 Hz), 3.92 (3H, s), 3.60 (2H, t, J=7.2 Hz), 3.01(2H, t, J=7.2 Hz), 2.58 (3H, s), 2.53 (1H, t, J=2.4 Hz)

Example 1463-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, 1.5 Hz), 7.59-7.55 (2H, m), 7.52 (1H, d,J=2.1 Hz), 7.45 (1H, d, J=2.1 Hz), 7.34-7.29 (1H, m), 5.97-5.85 (1H, m),5.23-5.09 (2H, m), 4.14 (2H, t, J=6.9 Hz), 3.91 (3H, s), 3.60 (2H, t,J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.68-2.57 (5H, m)

Example 1473-[2-(3-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.8 Hz), 7.59-7.51 (3H, m), 7.45 (1H,s), 7.34-7.30 (1H, m), 6.90 (1H, d, J=8.7 Hz), 4.09 (2H, t, J=6.6 Hz),3.90 (3H, s), 3.60 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.57 (3H,s), 1.86 (2H, td, J=7.2, 6.6 Hz), 1.56-1.45 (2H, m), 0.99 (3H, t, J=7.2Hz)

Example 1483-[2-(3-cyclohexylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.61-7.53 (2H, m), 7.49 (1H,d, J=1.8 Hz), 7.45 (1H, s), 7.34-7.28 (1H, m), 6.89 (1H, d, J=8.7 Hz),3.90-3.86 (5H, m), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57(3H, s), 1.94-1.85 (3H, m), 1.79-1.57 (3H, m), 1.38-0.88 (5H, m)

Example 1493-[2-(4-methoxy-3-(4-pentenyloxy)phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.59-7.54 (2H, m), 7.51(1H, d, J=2.1 Hz), 7.45 (1H, s), 7.34-7.29 (1H, m), 6.91 (1H, d, J=8.4Hz), 5.91-5.80 (1H, m), 5.11-4.97 (2H, m), 4.10 (2H, d, J=6.6 Hz), 3.91(3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s),2.30-2.22 (2H, m), 2.05-1.92 (2H, m)

Example 1503-[2-(4-methoxy-3-phenethyloxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.48 (1H, dd, J=4.5, 0.9 Hz), 7.60-7.49 (3H, m), 7.43(1H, s), 7.35-7.20 (6H, m), 6.91 (1H, d, J=8.7 Hz), 4.27 (2H, t, J=7.5Hz), 3.91 (3H, s), 3.58 (2H, t, J=7.2 Hz), 3.19 (2H, t, J=7.5 Hz), 3.00(2H, t, J=7.2 Hz), 2.55 (3H, s)

Example 1513-{2-[4-methoxy-3-(3-phenylpropoxy)phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.58 (1H, d, J=2.1 Hz),7.55 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=2.1 Hz), 7.44 (1H, s), 7.34-7.15(6H, m), 6.91 (1H, d, J=8.4 Hz), 4.11 (2H, t, J=6.6 Hz), 3.92 (3H, s),3.60 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.84 (2H, t, J=7.5 Hz),2.57 (3H, s), 2.20 (2H, tt, J=7.5, 6.6 Hz)

Example 152

Using 0.5 g of cyclopentylmethyl methanesulfonate obtained in ReferenceExample 52 and 0.2 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136, 90 mg of white powdery3-[2-(3-cyclopentylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained in the same manner as in Example137.

¹H-NMR (CDCl₃) δ: 8.49 (1H, d, J=3.9 Hz), 7.59-7.50 (3H, m), 7.45 (1H,s), 7.34-7.29 (1H, m), 6.90 (1H, d, J=8.4 Hz), 3.95 (2H, d, J=7.2 Hz),3.90 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H,s), 2.54-2.41 (1H, m), 1.91-1.82 (2H, m), 1.68-1.56 (4H, m), 1.42-1.24(2H, m)

Example 153

Using 0.16 g of 2-cyclopropylethyl methanesulfonate obtained inReference Example 50 and 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136, 0.1 g of white powdery3-{2-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtained in the same manner as in Example137.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, 1.5 Hz), 7.60-7.54 (3H, m), 7.46 (1H,s), 7.35-7.27 (1H, m), 6.91 (1H, d, J=8.1 Hz), 4.18 (2H, t, J=6.9 Hz),3.91 (3H, s), 3.61 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz), 2.58 (3H,s), 1.78 (2H, q, J=6.9 Hz), 0.91-0.80 (1H, m), 0.53-0.46 (2H, m),0.16-0.11 (2H, m)

Example 154

Using 0.19 g of 2-cyclopentylethyl methanesulfonate obtained inReference Example 51 and 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136, 0.13 g of white powdery3-{2-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtained in the same manner as in Example137.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.60-7.50 (3H, m), 7.45(1H, s), 7.34-7.30 (1H, m), 6.90 (1H, d, J=8.4 Hz), 4.10 (2H, t, J=6.9Hz), 3.92 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57(3H, s), 2.01-1.79 (5H, m), 1.67-1.50 (5H, m), 1.24-1.12 (2H, m)

Example 155

A 0.23 g quantity of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136 and 0.28 g of potassium carbonate were dissolvedin 5 ml of dimethylformamide. A 0.29 g quantity of1,1,1-trifluoro-2-iodoethane was added thereto, and the mixture wasstirred with heating at 80° C. overnight. The reaction mixture wasallowed to cool, water was then added thereto, and extraction wasperformed with ethyl acetate. After washing with water twice, theorganic layer was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography(dichloromethane:ethyl acetate=1:1) to give 0.14 g of white powdery3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 0.9 Hz), 7.70 (1H, dd, J=8.4, 2.1Hz), 7.60-7.56 (2H, m), 7.46 (1H, d, J=2.1 Hz), 7.35-7.30 (1H, m), 6.96(1H, d, J=8.4 Hz), 4.45 (2H, q, J=8.4 Hz), 3.92 (3H, s), 3.60 (2H, t,J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.57 (3H, s)

Example 156

Using 0.1 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136, 45 mg of pale yellow powdery3-{2-[4-methoxy-3-(3-methyl-2-butenyloxy)phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-onewas obtained in the same manner as in Example 155.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.59-7.52 (3H, m), 7.45(1H, s), 7.34-7.29 (1H, m), 6.90 (1H, d, J=8.4 Hz), 5.58-5.52 (1H, m),4.64 (2H, d, J=6.9 Hz), 3.91 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H,t, J=7.5 Hz), 2.57 (3H, s), 1.78 (3H, d, J=0.9 Hz), 1.77 (3H, s)

Example 157

Using 0.6 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136, 0.31 g of white powdery3-{2-[3-(2-cyclohexenyloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-onewas obtained in the same manner as in Example 155.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.60-7.56 (3H, m), 7.45(1H, s), 7.34-7.29 (1H, m), 6.91 (1H, d, J=9.0 Hz), 5.99-5.88 (2H, m),4.88 (1H, br s), 3.89 (3H, s), 3.60 (2H, t, J=7.2 Hz), 3.01 (2H, t,J=7.2 Hz), 2.57 (3H, s), 2.17-1.84 (5H, m), 1.71-1.61 (1H, m)

Example 158

A 0.3 g quantity of3-{2-[3-(2-cyclohexenyloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 157 was dissolved in 20 ml of ethanol. A 50 mgquantity of 10% palladium-carbon powder was added thereto, and themixture was stirred at room temperature for 2 hours. The catalyst wasremoved by filtration, and the filtrate was then concentrated. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1) to give 0.2 g of pale yellow oily3-[2-(3-cyclohexyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.59-7.54 (3H, m), 7.45 (1H,s), 7.34-7.30 (1H, m), 6.91 (1H, d, J=8.1 Hz), 4.35-4.25 (1H, m), 3.89(3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s),2.07-2.02 (2H, m), 1.84-1.80 (2H, m), 1.60-1.51 (4H, m), 1.43-1.23 (2H,m)

Example 159

A 0.26 g quantity of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 136 was dissolved in 10 ml of tetrahydrofuran. Tothe obtained solution were added 0.2 g of 2-hydroxyindane, 0.75 ml ofdiisopropyl azodicarboxylate (40% toluene solution) and 0.31 g oftri(n-butyl)phosphine, and the mixture was stirred at 50° C. After 3hours, 0.2 g of 2-hydroxyindan, 0.75 ml of diisopropyl azodicarboxylate(40% toluene solution) and 0.31 g of tri(n-butyl)phosphine were furtheradded thereto, and the mixture was stirred at 50° C. overnight. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (n-hexane:ethylacetate:dichloromethane=1:1:1), and recrystallized fromacetone/diisopropyl ether to give 0.13 g of colorless powdery3-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.51 (1H, br d, J=4.8 Hz), 7.62-7.16 (9H, m), 6.91(1H, d, J=8.7 Hz), 5.29 (1H, tt, J=6.6, 3.9 Hz), 3.85 (3H, s), 3.63 (2H,t, J=7.2 Hz), 3.45 (2H, dd, J=16.8, 6.6 Hz), 3.26 (2H, dd, J=16.8, 3.9Hz), 3.01 (2H, t, J=7.2 Hz), 2.58 (3H, s)

Example 160

A 2 g quantity of methyl3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate obtained inReference Example 48 and 1.5 g of methyl picolinate were dissolved in 40ml of dimethoxyethane. A 0.33 g quantity of sodium hydride was addedthereto with ice-cooling and stirring, and stirring was furthercontinued. The reaction mixture was heated and refluxed for 2 hours.After the reaction, an aqueous saturated ammonium chloride solution wasadded thereto with ice-cooling and stirring, and the mixture wasstirred. The reaction mixture was stirred for 30 minutes, water was thenadded thereto, and extraction was performed with ethyl acetate. Theorganic layer was washed twice with water and concentrated by removingthe solvent under reduced pressure. The obtained residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 2g of colorless oily methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-oxo-3-pyridin-2-ylpropionate.

¹H-NMR (CDCl₃) δ: 8.67 (1H, dd, J=4.2, 0.9 Hz), 8.07 (1H, dd, J=7.8, 2.1Hz), 7.83 (1H, td, J=7.8, 1.8 Hz), 7.55-7.30 (9H, m), 6.90 (1H, d, J=9.0Hz), 5.29 (1H, t, J=7.8 Hz), 5.16 (2H, s), 3.91 (3H, s), 3.66 (3H, s),3.36-3.28 (2H, m)

Example 161

Using 2 g of methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-oxo-3-(pyridin-2-yl)propionateobtained in Example 160, 0.48 g of white powdery3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-onewas obtained in the same manner as in Example 136.

¹H-NMR (CDCl₃) δ: 8.67 (1H, dd, J=4.2, 0.9 Hz), 8.05 (1H, dd, J=7.8, 2.1Hz), 7.83 (1H, td, J=7.8, 1.8 Hz), 7.55-7.43 (4H, m), 6.88 (1H, dd,J=7.8, 2.1 Hz), 5.72 (1H, s), 3.93 (3H, s), 3.64 (2H, t, J=7.5 Hz), 3.03(2H, t, J=7.5 Hz)

Example 162

A 0.15 g quantity of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-oneobtained in Example 161 and 0.2 ml of 1,8-diazabicyclo[5,4,0]undec-7-enewere dissolved in 5 ml of ethanol. A 0.14 g quantity of(bromomethyl)cyclobutane was added thereto, and the mixture was heatedand refluxed overnight. The reaction mixture was allowed to cool, waterwas then added thereto, and extraction was performed with ethyl acetate.After washing with water twice, the organic layer was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (dichloromethane:ethyl acetate=5:1) to give 50 mg ofwhite powdery3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.68 (1H, d, J=4.5 Hz), 8.05 (1H, d, J=7.8 Hz), 7.83(1H, td, J=7.8, 1.8 Hz), 7.58-7.44 (4H, m), 6.90 (1H, d, J=8.4 Hz), 4.07(2H, d, J=6.9 Hz), 3.89 (3H, s), 3.65 (2H, t, J=7.5 Hz), 3.05 (2H, t,J=7.5 Hz), 2.94-2.81 (1H, m), 2.24-2.04 (2H, m), 2.00-1.81 (4H, m)

Example 163

Using 0.3 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-oneobtained in Example 161, 0.28 g of white powdery3-[2-(4-methoxy-3-(4-pentenyloxy)phenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 8.69 (1H, dd, J=4.2, 1.5 Hz), 8.05 (1H, d, J=7.8 Hz),7.85 (1H, t, J=7.8 Hz), 7.60-7.46 (4H, m), 6.91 (1H, d, J=8.4 Hz),5.92-5.83 (1H, m), 5.11-4.99 (2H, m), 4.11 (2H, d, J=6.9 Hz), 3.91 (3H,s), 3.65 (2H, t, J=7.5 Hz), 3.05 (2H, t, J=7.5 Hz), 2.28-2.23 (2H, m),1.98 (2H, t, J=7.5 Hz)

Example 164

A 10 g quantity of 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazoleobtained in Reference Example 5 and 10.7 g of1-(2-allyloxyphenyl)ethanone obtained in Reference Example 53 weredissolved in 200 ml of tetrahydrofuran. A 1.82 g quantity of sodiumhydride was added thereto with ice-cooling and stirring, and stirringwas further continued. The reaction mixture was heated and refluxed for4 hours. After the reaction, an aqueous saturated ammonium chloridesolution was added thereto with ice-cooling and stirring, and themixture was stirred. After stirring for 30 minutes, water was addedthereto, and extraction was performed with ethyl acetate. The organiclayer was washed with water twice and concentrated by removing thesolvent under reduced pressure. The obtained residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=3:1) to give1.4 g of white powdery1-(2-allyloxyphenyl)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.62-7.58 (2H, m),7.49-7.30 (7H, m), 7.02-6.91 (3H, m), 6.12-6.02 (1H, m), 5.42 (1H, dd,J=17.4, 1.5 Hz), 5.30 (1H, dd, J=10.5, 1.5 Hz), 5.19 (2H, s), 4.65-4.62(2H, m), 3.92 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz)

Example 165

Using 1.4 g of1-(2-allyloxyphenyl)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propan-1-oneobtained in Example 164, 0.55 g of pale yellow oily3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-onewas obtained in the same manner as in Example 101.

¹H-NMR (CDCl₃) δ: 12.5 (1H, s), 7.81 (1H, dd, J=7.8, 1.5 Hz), 7.57-7.30(4H, m), 6.98 (1H, d, J=8.1 Hz), 6.92-6.86 (2H, m), 5.73 (1H, br s),3.94 (3H, s), 3.44 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz)

Example 166

Using 0.5 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-oneobtained in Example 165, 0.61 g of white powdery3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-allyloxyphenyl)propan-1-onewas obtained in the same manner as in Example 111.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 2.1 Hz), 7.58 (1H, dd, J=8.1, 2.1Hz), 7.52 (1H, d, J=2.1 Hz), 7.45-7.40 (2H, m), 7.02-6.90 (3H, m),6.16-6.03 (2H, m), 5.47-5.27 (4H, m), 4.68-4.62 (4H, m), 3.92 (3H, s),3.42 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz)

Example 167

Using 1.1 g of methyl3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate obtained inReference Example 48, 1 g of yellow oily methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-methoxyphenyl)-3-oxopropionatewas obtained in the same manner as in Example 100.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.57-7.53 (3H, m),7.48-7.30 (6H, m), 6.97 (1H, t, J=7.2 Hz), 6.91 (2H, d, J=7.8 Hz), 5.17(2H, s), 4.99 (1H, t, J=6.9 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.69 (3H,s), 3.27-3.19 (2H, m)

Example 168

Using 1 g of methyl2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-methoxyphenyl)-3-oxopropionateobtained in Example 167, 0.63 g of white powdery3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-onewas obtained in the same manner as in Example 101.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=8.4, 2.1 Hz), 7.56-7.52 (2H, m),7.44-7.41 (2H, m), 6.99-6.87 (3H, m), 3.95 (3H, s), 3.89 (3H, s), 3.38(2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz)

Example 169

Using 0.22 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-oneobtained in Example 168, 90 mg of colorless oily3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.70 (1H, d, J=7.5 Hz), 7.57 (1H, d, J=8.1 Hz), 7.54(1H, s), 7.47-7.40 (2H, m), 7.01-6.89 (3H, m), 4.67-4.62 (1H, m), 3.91(6H, s), 3.38 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.39 (6H, d,J=6.3 Hz)

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-oneobtained in Example 168, compounds of Examples 170 to 173 were obtainedin the same manner as in Example 102.

Example 1703-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.69-7.40 (4H, m), 6.99-6.89 (4H, m), 3.94-3.89 (8H,m), 3.37 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 1.40-1.35 (1H, m),0.67-0.65 (2H, m), 0.38-0.36 (2H, m)

Example 1713-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.56 (1H, dd, J=8.4, 2.1Hz), 7.51 (1H, s), 7.43 (1H, td, J=8.4, 1.8 Hz), 6.99-6.88 (3H, m), 4.48(1H, br s), 3.89 (3H, s), 3.88 (3H, s), 3.38 (2H, t, J=6.6 Hz), 2.98(2H, t, J=6.6 Hz), 2.04-1.85 (4H, m), 1.63-1.55 (4H, m)

Example 1723-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.57 (1H, dd, J=8.1, 2.1Hz), 7.51 (1H, d, J=1.8 Hz), 7.47-7.41 (2H, m), 7.01-6.89 (3H, m), 4.18(2H, q, J=7.8 Hz), 3.94 (3H, s), 3.90 (3H, s), 3.38 (2H, t, J=6.6 Hz),2.99 (2H, t, J=6.6 Hz), 1.49 (3H, t, J=7.8 Hz)

Example 173 3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.58-7.36 (4H, m),7.01-6.89 (3H, m), 3.90 (6H, s), 3.84 (2H, d, J=6.6 Hz), 3.38 (2H, t,J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz), 2.22-2.10 (1H, m), 1.05 (6H, d, J=6.6Hz)

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-oneobtained in Example 168, compounds of Examples 174 to 175 were obtainedin the same manner as in Example 111.

Example 1743-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.59 (1H, dd, J=8.4, 1.8Hz), 7.52 (1H, d, J=1.8 Hz), 7.48-7.41 (2H, m), 7.02-6.90 (3H, m),6.12-6.07 (1H, m), 5.43 (1H, dd, J=17, 1.5 Hz), 5.31 (1H, d, J=10 Hz),4.68 (2H, d, J=5.4 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.38 (2H, t, J=7.2Hz), 2.99 (2H, t, J=7.2 Hz)

Example 1751-(2-methoxyphenyl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propan-1-one

¹H-NMR (CDCl₃) δ: 7.69 (1H, dd, J=7.5, 1.8 Hz), 7.60 (1H, d, J=1.8 Hz),7.48-7.42 (2H, m), 7.02-6.95 (3H, m), 4.43 (2H, q, J=8.1 Hz), 3.92 (3H,s), 3.90 (3H, s), 3.38 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz)

Example 176

A 0.4 g quantity of sodium hydride was suspended in 20 ml oftetrahydrofuran, and 1.13 g of 1-(2-benzyloxy)ethanone and 1.46 g of4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole obtainedin Reference Example 11 were successively added thereto withice-cooling. The mixture was stirred for 4 hours with heating andrefluxing. An aqueous saturated ammonium chloride solution was added tothe reaction mixture with ice cooling. After stirring for 15 minutes,water was added thereto, and extraction was performed with ethylacetate. Drying was performed with anhydrous magnesium sulfate, and thesolvent was removed. Purification was performed using a silica gelcolumn (n-hexane:ethyl acetate=4:1), and the obtained compound wasdissolved in 12 ml of ethanol. A 35 mg quantity of 10% palladium-carbonpowder was added thereto, and stirring was performed under a hydrogenatmosphere overnight. The catalyst was removed by filtration and theobtained filtrate was concentrated. The residue was purified using asilica gel column (n-hexane:ethyl acetate=4:1) to give 0.43 g of whitepowdery3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 12.2 (1H, s), 7.83 (1H, d, J=1.5 Hz), 7.80-7.44 (4H,m), 7.00-6.87 (3H, m), 3.94-3.92 (5H, m), 3.44 (2H, t, J=7.2 Hz), 3.03(2H, t, J=7.2 Hz), 1.37-1.26 (1H, m), 0.70-0.65 (2H, m), 0.41-0.37 (2H,m)

Example 177

A 2 g quantity of 4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole obtained in Reference Example 11 and 3.6g of 1-(2-allyloxyphenyl)ethanone obtained in Reference Example 53 weredissolved in 40 ml of tetrahydrofuran. A 0.55 g quantity of sodiumhydride was added thereto with ice-cooling and stirring, and the mixturewas stirred. The reaction mixture was heated and refluxed for 6 hours.After the reaction completion, an aqueous saturated ammonium chloridesolution was added thereto with ice-cooling, and the mixture wasstirred. The reaction mixture was stirred for 30 minutes, water was thenadded thereto, and extraction was performed with ethyl acetate. Theorganic layer was washed with water twice and concentrated by removingthe solvent under reduced pressure. The obtained residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=3:1) to give0.5 g of while powdery1-(2-allyloxyphenyl)-3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.57 (1H, dd, J=8.4, 2.1Hz), 7.49 (1H, d, J=2.1 Hz), 7.45-7.39 (2H, m), 7.02-6.89 (3H, m),6.09-6.02 (1H, m), 5.45-5.26 (2H, m), 4.65-4.62 (2H, m), 3.94-3.91 (5H,m), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.45-1.35 (1H, m),0.68-0.62 (2H, m), 0.40-0.36 (2H, m)

Example 178

Using 1.4 g of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole obtained inReference Example 35 and 0.88 g of 1-(2-allyloxyphenyl)ethanone obtainedin Reference Example 53, 0.42 g of white powdery1-(2-allyloxyphenyl)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propan-1-onewas obtained in the same manner as in Example 177.

¹H-NMR (CDCl₃) δ: 7.69 (1H, dd, J=7.5, 2.1 Hz), 7.56-7.51 (2H, m),7.45-7.39 (2H, m), 7.02-6.89 (3H, m), 6.14-6.01 (1H, m), 5.42 (1H, dd,J=17, 1.5 Hz), 5.29 (1H, dd, J=10.5, 1.5 Hz), 4.65-4.62 (2H, m),4.20-4.10 (4H, m), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.50(6H, t, J=7.2 Hz)

Example 179

Using 0.31 g of 1-(2-chlorophenyl)ethanone and 0.59 g of4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole obtainedin Reference Example 11, 0.11 g of colorless oily1-(2-chlorophenyl)-3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained in the same manner as in Example 177.

¹H-NMR (CDCl₃) δ: 7.60-7.55 (2H, m), 7.49-7.43 (2H, m), 7.40 (1H, s),7.39-7.30 (2H, m), 6.91 (1H, d, J=8.7 Hz), 3.94-3.91 (5H, m), 3.36 (2H,t, J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz), 1.37-1.29 (1H, m), 0.69-0.63 (2H,m), 0.40-0.37 (2H, m)

Example 180

Using 2 g of methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionateobtained in Reference Example 54 and 1.3 g of ethyl 3-methylpicolinate,0.8 g of yellow oily methyl2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionatewas obtained in the same manner as in Example 124.

¹H-NMR (CDCl₃) δ: 8.50 (1H, m), 7.60-7.40 (4H, m), 7.30 (1H, m), 6.88(1H, d, J=8.4 Hz), 5.20 (1H, t, J=7.2 Hz), 4.20-4.05 (4H, m), 2.99 (3H,s), 3.35-3.20 (2H, m), 2.59 (3H, s), 1.47 (3H, t, J=6.9 Hz), 1.47 (3H,t, J=6.9 Hz)

Example 181

A 0.8 g quantity or methyl2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionateobtained in Example 180 was added to a mixture of 5 ml acetic acid and1.5 ml of concentrated hydrochloric acid, and the resulting mixture wasstirred at 110° C. for 4 hours. After cooling the obtained solution toroom temperature, 30 ml of ethyl acetate and 30 ml of saturated sodiumhydrogen carbonate solution were gradually added thereto with stirring,and stirring was further continued. The organic layer was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate:n-hexane=3:1), and further recrystallized from ethylacetate/n-hexane to give 0.28 g of white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.49 (1H, m), 7.60-7.50 (3H, m), 7.44 (1H, s), 7.32(1H, m), 6.90 (1H, d, J=8.1 Hz), 4.17 (2H, q, J=6.9 Hz), 4.13 (2H, q,J=6.9 Hz), 3.51 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.57 (3H, s),1.48 (3H, t, J=6.9 Hz), 1.47 (3H, t, J=6.9 Hz)

Example 182

A 2 g quantity of methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionateobtained in Reference Example 54 and 1.5 g of ethyl 2-ethoxybenzoatewere dissolved in 10 ml of dimethylformamide. A 1.81 g quantity ofsodium t-pentoxide was added thereto with ice-cooling and stirring, andthe mixture was stirred for 30 minutes. The reaction mixture was furtherstirred at room temperature for 5 hours, and ice was added thereto. Anaqueous saturated ammonium chloride solution was added thereto, and themixture was stirred. The reaction mixture was stirred for 30 minutes,water was then added thereto, and extraction was performed with ethylacetate. The organic layer was washed with water twice and concentratedby removing the solvent under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1). The obtained yellow oily substance was added to a mixtureof 5 ml of acetic acid and 1.5 ml of concentrated hydrochloric acid, andthe resulting mixture was stirred at 110° C. for 4 hours. After coolingthe mixture to room temperature, 30 ml of ethyl acetate and 30 ml ofsaturated sodium hydrogen carbonate solution were gradually addedthereto with stirring, and stirring was further continued. The organiclayer was dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane=3:1), and the obtained crudecrystals were recrystallized from ethyl acetate/n-hexane to give 0.46 gof white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 2.1 Hz), 7.60-7.50 (2H, m),7.45-7.35 (2H, m), 7.00-6.80 (2H, m), 4.17 (2H, q, J=7.2 Hz), 4.13 (2H,q, J=7.2 Hz), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.48 (3H,t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Using methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate obtained inReference Example 54, compounds of Example 183 to 185 were obtained inthe same manner as in Example 182.

Example 1833-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-ethoxypyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.23 (1H, dd, J=4.5, 1.2 Hz), 7.55-7.50 (2H, m),7.40-7.25 (2H, m), 7.45 (1H, s), 6.90 (1H, d, J=8.1 Hz), 4.20-4.05 (6H,m), 3.49 (2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz), 1.47 (3H, t, J=7.2Hz), 1.47 (3H, t, J=7.2 Hz), 1.46 (3H, t, J=7.2 Hz)

Example 1843-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.00-7.95 (2H, m), 7.60-7.50 (2H, m), 7.43 (1H, s),6.95-6.85 (3H, m), 4.17 (2H, q, J=7.2 Hz), 4.17 (2H, q, J=7.2 Hz), 4.09(2H, q, J=7.2 Hz), 3.34 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 1.48(3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.44 (3H, t, J=7.2 Hz).

Example 1853-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(4-ethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.60-7.50 (4H, m), 7.44 (1H, s), 7.35 (1H, t, J=7.8Hz), 7.09 (1H, dd, J=9.0, 2.4 Hz), 6.10 (1H, d, J=5.4 Hz), 4.16 (2H, q,J=7.2 Hz), 4.15 (2H, q, J=7.2 Hz), 4.08 (2H, q, J=7.2 Hz), 3.38 (2H, t,J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 1.48 (3H, t,J=7.2 Hz), 1.40 (3H, t, J=7.2 Hz).

Example 186

Using 2 g of dimethyl2-[2-(3,4-bis(benzyloxy)phenyl)oxazol-4-ylmethyl]malonate obtained inReference Example 56, 2.2 g of pale yellow oily methyl2-[2-(3,4-bisbenzyloxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionatewas obtained in the same manner as in Example 100.

¹H-NMR (CDCl₃) δ: 8.49 (1H, dd, J=4.5, 1.2 Hz), 7.59-7.28 (15H, m), 6.94(1H, d, J=8.4 Hz), 5.23-5.17 (5H, m), 3.69 (3H, s), 3.32-3.23 (2H, m),2.59 (3H, s)

Example 187

Using 2.2 g of methyl2-[2-(3,4-bisbenzyloxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionateobtained in Example 186, 0.24 g of white powdery3-[2-(3,4-dihydroxyphenyl)oxazol-4-ylmethyl]-1-(3-methylpyridin-2-yl)propan-1-onewas obtained in the same manner as in Example 136.

¹H-NMR (CDCl₃) δ: 9.46 (1H, br s), 9.32 (1H, br s), 8.54 (1H, d, J=3.0Hz), 7.80-7.76 (2H, m), 7.54-7.49 (1H, m), 7.32 (1H, d, J=2.1 Hz), 7.23(1H, dd, J=8.4, 2.1 Hz), 6.82 (1H, d, J=8.4 Hz), 3.47 (2H, t, J=7.5 Hz),2.83 (2H, t, J=7.5 Hz), 2.51 (3H, s)

Example 188

Using 0.12 g of3-[2-(3,4-dihydroxyphenyl)oxazol-4-ylmethyl]-1-(3-methylpyridin-2-yl)propan-1-oneobtained in Example 187, 35 mg of white powdery3-{2-[3,4-bis-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-onewas obtained in the same manner as in Example 111.

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.68 (1H, dd, J=8.4, 1.8 Hz),7.63 (1H, d, J=1.8 Hz), 7.58 (1H, d, J=8.4 Hz), 7.49 (1H, s), 7.35-7.28(1H, m), 7.04 (1H, d, J=8.4 Hz), 4.50-4.39 (4H, m), 3.60 (2H, t, J=7.2Hz), 3.01 (2H, t, J=7.2 Hz), 2.59 (3H, s)

Example 189

Using 0.76 g of 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazoleobtained in Reference Example 58 and 0.5 g of1-(2-allyloxyphenyl)ethanone obtained in Reference Example 53, 0.13 g ofwhite powdery1-(2-allyloxyphenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained in the same manner as in Example 177.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 2.1 Hz), 7.56 (1H, dd, J=8.4, 2.1Hz), 7.51 (1H, d, J=2.1 Hz), 7.45-7.40 (2H, m), 7.02-6.89 (3H, m),6.12-6.01 (1H, m), 5.42 (1H, dd, J=17, 1.5 Hz), 5.28 (1H, dd, J=17, 1.5Hz), 4.65-4.62 (2H, m), 4.18 (2H, q, J=6.9 Hz), 3.92 (3H, s), 3.42 (2H,t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.49 (3H, t, J=6.9 Hz)

Example 190

A 2 g quantity of 4-chloromethyl-2-(4-benzyloxy-3-ethoxyphenyl)oxazoleobtained in Reference Example 63 and 0.96 g of1-(2-ethoxyphenyl)ethanone were dissolved in 20 ml of tetrahydrofuran,and 0.47 g sodium hydride was added thereto. After foaming, the reactionmixture was heated and refluxed for 3 hours. After cooling, the reactionmixture was added to ice water, and extraction was performed with ethylacetate. The organic layer was washed with water, dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=3:1) to give 0.4 g of colorless powdery3-[2-(4-benzyloxy-3-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.55-7.30 (8H, m), 6.97(2H, t, J=7.5 Hz), 6.93 (1H, d, J=7.5 Hz), 5.19 (2H, s), 4.18 (2H, q,J=6.9 Hz), 4.13 (2H, q, J=6.9 Hz), 3.41 (2H, t, J=6.9 Hz), 2.99 (2H, t,J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz), 1.47 (3H, t, J=6.9 Hz)

Example 191

Using3-[2-(4-benzyloxy-3-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-oneobtained in Example 190, colorless oily3-[2-(3-ethoxy-4-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained in the same manner as in Example 2.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.52 (1H, dd, J=8.1, 2.1Hz), 7.49 (1H, d, J=2.1 Hz), 7.45-7.38 (2H, m), 6.97 (1H, t, J=7.5 Hz),6.95 (1H, d, J=7.5 Hz), 6.93 (1H, d, J=8.1 Hz), 5.89 (1H, s), 4.20 (2H,q, J=7.2 Hz), 4.13 (2H, q, J=7.2 Hz), 3.41 (2H, t, J=7.2 Hz), 2.98 (2H,t, J=7.2 Hz), 1.47 (3H, t, J=7.2 Hz), 1.47 (3H, t, J=7.2 Hz)

Example 192

Using3-[2-(3-ethoxy-4-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-oneobtained in Example 191, colorless needle crystalline3-[2-(3-ethoxy-4-isopropoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-onewas obtained in the same manner as in Example 111.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.54-7.51 (2H, m),7.45-7.39 (2H, m), 6.97 (2H, br t, J=7.5 Hz), 6.93 (1H, d, J=7.5 Hz),4.55 (1H, sept, J=6.0 Hz), 4.14 (2H, q, J=6.9 Hz), 4.13 (2H, q, J=6.9Hz), 3.42 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 1.47 (3H, t, J=6.9Hz), 1.45 (3H, t, J=6.9 Hz), 1.37 (6H, d, J=6.0 Hz)

Example 193

A 2.98 g quantity of2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde obtained inReference Example 64 and 1.72 g of 1-(2-propoxyphenyl)ethanone weredissolved in 50 ml of pyridine. A 2.66 g quantity of potassium carbonatewas added thereto, and the mixture was heated and stirred at 120° C. for22 hours. After cooling, the reaction mixture was added to saturatedbrine, and extraction was performed with ethyl acetate. The organiclayer was washed with water and then dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=3:1) to give 1.82 g of colorless oily(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2-propen-1-one.

¹H-NMR (CDCl₃) δ: 7.80 (1H, s), 7.79 (1H, d, J=15.3 Hz), 7.69-7.66 (3H,m), 7.51-7.32 (7H, m), 7.04-6.95 (3H, m), 5.21 (2H, s), 4.05 (2H, t,J=6.3 Hz), 3.94 (3H, s), 1.88 (2H, sext., J=6.3 Hz), 1.08 (3H, t, J=6.3Hz)

Example 194

A 1.82 g quantity of(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2-propen-1-oneobtained in Example 193 was dissolved in 50 ml of methanol. A 200 mgquantity of 5% palladium-carbon powder was added thereto, and themixture was stirred under a hydrogen atmosphere at room temperature for2 hours. The catalyst was then removed by filtration. The filtrate wasdiluted with 100 ml of methanol, and 500 mg of 10% palladium-carbonpowder was added thereto. The mixture was stirred under a hydrogenatmosphere at room temperature for 3 hours. The catalyst was removed byfiltration, and the solvent was removed under reduced pressure.Diisopropyl ether was added to the residue for crystallization to give0.78 g of colorless powdery3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.55 (1H, d, J=2.1 Hz),7.53 (1H, dd, J=8.1, 2.1 Hz), 7.42 (1H, ddd, J=8.1, 7.5, 1.8 Hz), 7.40(1H, s), 6.97 (1H, td, J=7.5, 0.9 Hz), 6.93 (1H, br d, J=8.1 Hz), 6.89(1H, d, J=8.1 Hz), 4.02 (2H, t, J=6.6 Hz), 3.94 (3H, s), 3.43 (2H, t,J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.88 (2H, sext., J=6.6 Hz), 1.06 (3H,t, J=6.6 Hz)

Example 195

Using 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-oneobtained in Example 194, 67 mg of colorless powdery3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.59-7.40 (4H, m), 6.97(1H, t, J=7.8 Hz), 6.94 (1H, d, J=7.8 Hz), 6.91 (1H, d, J=7.8 Hz), 4.18(2H, q, J=6.6 Hz), 4.02 (2H, t, J=6.6 Hz), 3.92 (3H, s), 3.43 (2H, t,J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.87 (2H, sext., J=6.6 Hz), 1.49 (3H,t, J=6.6 Hz), 1.06 (3H, t, J=6.6 Hz)

Example 196

Using 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-oneobtained in Example 194, 67 mg of colorless oily3-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.5, 1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8Hz), 7.51 (1H, d, J=1.8 Hz), 7.42 (1H, br t, J=7.5 Hz), 7.39 (1H, s),6.97 (1H, t, J=7.5 Hz), 6.93 (1H, d, J=7.5 Hz), 6.89 (1H, d, J=8.4 Hz),4.90-4.84 (1H, m), 4.02 (2H, t, J=6.6 Hz), 3.88 (3H, s), 3.43 (2H, t,J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.03-1.60 (10H, m), 1.05 (3H, t,J=7.2 Hz)

Example 197

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-oneobtained in Example 194, colorless oily3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-one was obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.57 (1H, dd, J=8.4, 2.1Hz), 7.54 (1H, d, J=2.1 Hz), 7.42 (1H, ddd, J=8.4, 7.2, 1.8 Hz), 7.39(1H, s), 6.97 (1H, br t, J=7.2 Hz), 6.96 (1H, br d, J=8.4 Hz), 6.91 (1H,d, J=8.4 Hz), 4.65 (1H, sept., J=6.0 Hz), 4.02 (2H, t, J=7.2 Hz), 3.90(3H, s), 3.43 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.87 (2H,sext., J=7.2 Hz), 1.40 (6H, d, J=6.0 Hz), 1.06 (3H, t, J=7.2 Hz)

Example 198

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-oneobtained in Example 194, colorless powdery3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.57 (1H, dd, J=8.4, 1.8Hz), 7.50 (1H, d, J=1.8 Hz), 7.45-7.39 (2H, m), 6.97 (1H, br t, J=7.5Hz), 6.93 (1H, br d, J=7.5 Hz), 6.91 (1H, br d, J=8.4 Hz), 4.02 (2H, t,J=6.6 Hz), 3.92 (2H, d, J=7.2 Hz), 3.92 (3H, s), 3.43 (2H, t, J=7.2 Hz),2.99 (2H, t, J=7.2 Hz), 1.87 (2H, sext., J=6.6 Hz), 1.41-1.32 (1H, m),1.06 (3H, t, J=6.6 Hz), 0.69-0.63 (2H, m), 0.40-0.35 (2H, m)

Example 199

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-oneobtained in Example 194, colorless needle crystalline3-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.7, 1.5 Hz), 7.58 (1H, dd, J=8.5, 2.0Hz), 7.52 (1H, d, J=2.0 Hz), 7.42 (1H, ddd, J=7.7, 7.5, 1.8 Hz), 7.40(1H, s), 6.97 (1H, ddd, J=7.7, 7.5, 0.9 Hz), 6.93 (1H, br d, J=7.7 Hz),6.91 (1H, d, J=8.5 Hz), 5.92 (1H, ddt, J=17.3, 10.3, 6.8 Hz), 5.19 (1H,ddd, J=17.3, 3.3, 1.5 Hz), 5.11 (1H, ddd, J=10.3. 3.3, 0.6 Hz), 4.14(2H, t, J=7.2 Hz), 4.02 (2H, t, J=7.2 Hz), 3.91 (3H, s), 3.43 (2H, t,J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.63 (2H, br q, J=6.9 Hz), 1.87 (2H,sext., J=7.2 Hz), 1.06 (3H, t, J=7.2 Hz)

Example 200

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-oneobtained in Example 194, colorless needle crystalline3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.7, 1.8 Hz), 7.59 (1H, dd, J=8.5, 1.8Hz), 7.52 (1H, d, J=1.8 Hz), 7.42 (1H, ddd, J=8.3, 7.7, 1.8 Hz), 7.40(1H, s), 6.97 (1H, td, J=7.7, 1.1 Hz), 6.93 (1H, br d, J=8.3 Hz), 6.91(1H, d, J=8.5 Hz), 6.12 (1H, ddt, J=17.3, 10.5, 5.5 Hz), 5.44 (1H, ddd,J=17.3, 3.0, 1.5 Hz), 5.31 (1H, ddd, J=10.5. 3.0, 1.5 Hz), 4.67 (2H, dt,J=5.5, 1.5 Hz), 4.02 (2H, t, J=6.3 Hz), 3.92 (3H, s), 3.43 (2H, t, J=7.2Hz), 2.99 (2H, t, J=7.2 Hz), 1.87 (2H, sext., J=6.3 Hz), 1.06 (3H, t,J=6.3 Hz)

Example 201

Using 0.1 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-oneobtained in Example 194, 67 mg of colorless powdery3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-one was obtained in thesame manner as in Example 111.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.56 (1H, dd, J=7.8, 1.8Hz), 7.52 (1H, d, J=1.8 Hz), 7.45-7.40 (2H, m), 6.98 (1H, t, J=7.8 Hz),6.94 (1H, d, J=7.8 Hz), 6.90 (1H, d, J=7.8 Hz), 4.07 (2H, d, J=6.9 Hz),4.02 (2H, t, J=6.6 Hz), 3.90 (3H, s), 3.44 (2H, t, J=7.2 Hz), 3.00 (2H,t, J=7.2 Hz), 2.86 (1H, quint, J=7.2 Hz), 2.21-2.16 (2H, m), 1.96-1.84(6H, m), 1.06 (3H, t, J=7.5 Hz)

Example 202

Using2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazole-4-carbaldehydeobtained in Reference Example 65, pale yellow oily(E)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(2-propoxyphenyl)-2-propen-1-onewas obtained in the same manner as in Example 193.

¹H-NMR (CDCl₃) δ: 7.83 (1H, d, J=15.0 Hz), 7.81 (1H, s), 7.76 (1H, dd,J=8.4, 2.1 Hz), 7.69 (1H, dd, J=7.8, 1.8 Hz), 7.69 (1H, d, J=2.1 Hz),7.50 (1H, d, J=15.0 Hz), 7.45 (1H, ddd, J=8.4, 7.8, 1.8 Hz), 7.01 (1H,br t, J=8.4 Hz), 6.99 (1H, d, J=8.4 Hz), 6.98 (1H, br d, J=7.8 Hz), 4.46(2H, q, J=8.4 Hz), 4.06 (2H, t, J=6.3 Hz), 3.94 (3H, s), 1.90 (2H,sext., J=6.3 Hz), 1.09 (3H, t, J=6.3 Hz)

Example 203

Using(E)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(2-propoxyphenyl)-2-propen-1-oneobtained in Example 202, colorless powdery3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(2-propoxyphenyl)propan-1-onewas obtained in the same manner as in Example 194.

¹H-NMR (DMSO-d₆) δ: 7.83 (1H, s), 7.62 (1H, dd, J=7.8, 1.8 Hz), 7.57(1H, dd, J=7.8, 1.5 Hz), 7.55 (1H, d, J=1.5 Hz), 7.51 (1H, br t, J=7.8Hz), 7.17 (1H, d, J=7.8 Hz), 7.15 (1H, d, J=7.8 Hz), 7.01 (1H, t, J=7.8Hz), 4.80 (2H, q, J=9.0 Hz), 4.06 (2H, t, J=6.6 Hz), 3.86 (3H, s), 3.33(2H, t, J=7.2 Hz), 2.84 (2H, t, J=7.2 Hz), 1.79 (2H, sext., J=6.6 Hz),0.99 (3H, t, J=6.6 Hz)

Example 204

Using 2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde obtained in ReferenceExample 66, pale yellow powdery(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2-propen-1-onewas obtained in the same manner as in Example 193.

¹H-NMR (CDCl₃) δ: 7.81 (1H, d, J=15.0 Hz), 7.79 (1H, br d, J=7.5 Hz),7.68 (1H, dd, J=7.8, 1.8 Hz), 7.62 (1H, d, J=1.8 Hz), 7.59 (1H, br s),7.49 (1H, d, J=15.0 Hz), 7.44 (1H, br t, J=7.5 Hz), 7.01 (1H, br t,J=7.5 Hz), 6.97 (1H, br d, J=7.5 Hz), 6.93 (1H, d, J=7.8 Hz), 4.18 (2H,q, J=6.9 Hz), 4.16 (2H, q, J=6.9 Hz), 4.05 (2H, t, J=6.3 Hz), 1.89 (1H,br sext., J=6.9 Hz), 1.50 (3H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz),1.09 (3H, t, J=7.2 Hz)

Example 205

Using(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2-propen-1-oneobtained in Example 204, colorless powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-onewas obtained in the same manner as in Example 194.

¹H-NMR (CDCl₃) δ: 7.60 (1H, dd, J=7.8, 1.8 Hz), 7.54 (1H, dd, J=8.4, 2.1Hz), 7.52 (1H, d, J=2.1 Hz), 7.42 (1H, ddd, J=7.8, 7.2, 1.8 Hz), 7.39(1H, s), 6.97 (1H, td, J=7.8, 1.2 Hz), 6.93 (1H, br d, J=7.2 Hz), 6.90(1H, d, J=8.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 4.02(2H, t, J=6.6 Hz), 3.43 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.87(2H, sept., J=6.6 Hz), 1.48 (6H, t, J=6.9 Hz), 1.05 (3H, t, J=6.6 Hz)

Example 206

Using 2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde obtained inReference Example 64, pale yellow powdery(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-2-propen-1-onewas obtained in the same manner as in Example 193.

¹H-NMR (CDCl₃) δ: 7.79 (1H, s), 7.79 (1H, d, J=15.3 Hz), 7.69-7.65 (3H,m), 7.50-7.32 (7H, m), 7.03-6.95 (3H, m), 5.21 (2H, s), 4.66 (1H, sept,J=6.0 Hz), 3.94 (3H, s), 1.41 (6H, d, J=6.0 Hz)

Example 207

Using(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-2-propen-1-oneobtained in Example 206, colorless powdery3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas obtained in the same manner as in Example 194.

¹H-NMR (CDCl₃) δ: 7.67 (1H, dd, J=7.5, 1.8 Hz), 7.55 (1H, br s), 7.54(1H, dd, J=7.5, 1.8 Hz), 7.40 (1H, td, J=7.5, 1.8 Hz), 7.40 (1H, s),6.95 (1H, br t, J=7.5 Hz), 6.93 (1H, br d, J=7.5 Hz), 6.89 (1H, d, J=7.5Hz), 5.64 (1H, s), 4.68 (1H, sept., J=6.0 Hz), 3.94 (3H, s), 3.40 (2H,t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.40 (6H, d, J=6.0 Hz)

The above compound was also obtained by the following method. A 10 gquantity of 2-(3-benzyloxy-4-methoxyphenyl-4-chloromethyloxazoleobtained in Reference Example 5 and 5.4 g of1-(2-isopropoxyphenyl)ethanone were dissolved in 100 ml oftetrahydrofuran, and 2.42 g of sodium hydride was added thereto. Afterfoaming, the reaction mixture was heated and refluxed for 3 hours. Aftercooling, the reaction mixture was added to ice water, and extraction wasperformed with ethyl acetate. The organic layer was washed with water,dried over magnesium sulfate, and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1) to give 4.30 g of pale yellow oily3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-one.Subsequently, 1.84 g of the obtained3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas dissolved in 100 ml of methanol. An 800 mg quantity of 10%palladium-carbon powder was added thereto. The mixture was stirred undera hydrogen atmosphere at room temperature for 1 hour. The catalyst wasremoved by filtration, and the solvent was removed. The residue was thenrecrystallized from acetone/diisopropyl ether to give 1.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-one.

Example 208

Using 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-oneobtained in Example 207, 0.12 g of pale yellow oily3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.67 (1H, dd, J=7.8, 1.8 Hz), 7.57 (1H, dd, J=8.4, 2.1Hz), 7.50 (1H, d, J=2.1 Hz), 7.41 (1H, td, J=7.8, 1.8 Hz), 7.39 (1H, s),6.95 (1H, br t, J=7.8 Hz), 6.93 (1H, br d, J=7.8 Hz), 6.91 (1H, d, J=8.4Hz), 4.68 (1H, sept., J=6.0 Hz), 3.92 (2H, d, J=6.9 Hz), 3.92 (3H, s),3.41 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.40 (6H, d, J=6.0 Hz),1.46-1.32 (1H, m), 0.69-0.62 (2H, m), 0.40-0.35 (2H, m)

Example 209

Using 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-oneobtained in Example 207, 42 mg of colorless powdery3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=7.7, 1.8 Hz), 7.57 (1H, dd, J=8.5, 2.0Hz), 7.52 (1H, d, J=2.0 Hz), 7.41 (1H, td, J=7.7, 1.8 Hz), 7.40 (1H, s),6.95 (1H, br t, J=7.7 Hz), 6.94 (1H, br d, J=7.7 Hz), 6.91 (1H, d, J=8.5Hz), 4.69 (1H, sept., J=6.0 Hz), 4.18 (2H, q, J=6.9 Hz), 3.92 (3H, s),3.41 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz),1.40 (6H, d, J=6.0 Hz)

Example 210

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-oneobtained in Example 207, pale yellow oily3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=7.5, 1.8 Hz), 7.57 (1H, dd, J=7.5, 1.8Hz), 7.54 (1H, d, J=1.8 Hz), 7.44-7.38 (2H, m), 6.95 (1H, br t, J=7.5Hz), 6.94 (1H, d, J=7.5 Hz), 6.91 (1H, d, J=7.5 Hz), 4.67 (2H, sept.,J=6.0 Hz), 3.90 (3H, s), 3.40 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz),1.40 (12H, d, J=6.0 Hz)

Example 211

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-oneobtained in Example 207, colorless oily3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=7.7, 1.8 Hz), 7.58 (1H, dd, J=8.3, 1.8Hz), 7.53 (1H, d, J=1.8 Hz), 7.41 (1H, ddd, J=7.9, 7.7, 1.8 Hz), 7.40(1H, s), 6.98 (1H, td, J=7.9, 1.8 Hz), 6.94 (1H, br d, J=7.7 Hz), 6.92(1H, d, J=8.3 Hz), 6.12 (1H, ddt, J=17.3, 10.5, 5.3 Hz), 5.44 (1H, ddd,J=17.3, 3.0, 1.7 Hz), 5.31 (1H, ddd, J=10.5. 3.0, 1.5 Hz), 4.75-4.60(3H, m), 3.92 (3H, s), 3.41 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz),1.40 (6H, d, J=6.0 Hz).

Example 212

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-oneobtained in Example 207, colorless needle crystalline3-[2-(3-(3-butenyloxy)-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.67 (1H, dd, J=7.9, 1.8 Hz), 7.57 (1H, dd, J=8.5, 2.0Hz), 7.53 (1H, d, J=2.0 Hz), 7.40 (1H, ddd, J=7.9, 7.5, 1.8 Hz), 7.40(1H, s), 6.95 (1H, br t, J=7.5 Hz), 6.93 (1H, br d, J=7.5 Hz), 6.91 (1H,d, J=8.5 Hz), 5.92 (1H, ddt, J=17.1, 10.3, 6.8 Hz), 5.19 (1H, ddd,J=17.3, 3.3, 1.5 Hz), 3.51 (1H, ddd, J=10.3. 3.3, 1.3 Hz), 4.68 (1H,sept., J=6.0 Hz), 4.14 (2H, t, J=7.2 Hz), 3.91 (3H, s), 3.41 (2H, t,J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.63 (2H, br q, J=7.2 Hz), 1.40 (6H,d, J=6.0 Hz)

Example 213

Using 0.15 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-oneobtained in Example 207, 40 mg of colorless powdery1-(2-isopropoxyphenyl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propan-1-onewas obtained in the same manner as in Example 111.

¹H-NMR (CDCl₃) δ: 7.70-7.60 (2H, m), 7.44-7.38 (2H, m), 6.98-6.91 (4H,m), 4.69 (1H, sept., J=6.0 Hz), 4.48-4.41 (2H, m), 3.93 (3H, s), 3.42(2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.41 (6H, d, J=6.0 Hz)

Example 214

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-oneobtained in Example 207, colorless powdery3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-onewas obtained in the same manner as in Example 111.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=8.4, 1.8 Hz), 7.56 (1H, dd, J=8.4, 1.8Hz), 7.52 (1H, d, J=1.8 Hz), 7.44-7.38 (2H, m), 6.95 (1H, br t, J=8.4Hz), 6.94 (1H, br d, J=8.4 Hz), 6.90 (1H, d, J=8.4 Hz), 4.69 (1H, sept.,J=6.0 Hz), 4.07 (2H, d, J=6.9 Hz), 3.90 (3H, s), 3.41 (2H, t, J=7.2 Hz),2.99 (2H, t, J=7.2 Hz), 2.86 (1H, quint, J=7.2 Hz), 2.22-2.14 (2H, m),1.99-1.84 (4H, m), 1.40 (6H, d, J=6.0 Hz)

Example 215

Using 2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde obtained in ReferenceExample 66, yellow oily(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-2-propen-1-onewas obtained in the same manner as in Example 193.

¹H-NMR (CDCl₃) δ: 7.81 (1H, d, J=15.3 Hz), 7.79 (1H, br s), 7.69-7.53(3H, m), 7.46 (1H, d, J=15.3 Hz), 7.43 (1H, td, J=7.8, 1.2 Hz), 7.00(1H, br t, J=7.8 Hz), 6.93 (1H, br d, J=7.8 Hz), 6.91 (1H, br d, J=7.8Hz), 4.67 (1H, sept, J=6.0 Hz), 4.22-4.11 (4H, m), 1.52-1.45 (6H, m),1.41 (6H, d, J=6.0 Hz)

Example 216

Using(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)-2-propen-1-oneobtained in Example 215, pale yellow oily3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-one was obtained in the same manner as in Example 194.

¹H-NMR (CDCl₃) δ: 7.67 (1H, dd, J=7.5, 1.5 Hz), 7.60-7.38 (4H, m),6.97-6.89 (3H, m), 4.68 (1H, sept, J=6.0 Hz), 4.21-4.10 (4H, m), 3.41(2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.48 (6H, br t, J=7.2 Hz),1.40 (6H, d, J=6.0 Hz)

Example 217

Using 2-(3,4-diethoxyphenyl)oxazole-4-carbaldehyde obtained in ReferenceExample 66, colorless powdery(E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-propen-1-one wasobtained in the same manner as in Example 193.

¹H-NMR (CDCl₃) δ: 7.81 (1H, s), 7.64-7.28 (8H, m), 6.93 (1H, d, J=8.1Hz), 4.20 (2H, q, J=6.9 Hz), 4.16 (2H, q, J=6.9 Hz), 2.47 (3H, s), 1.50(3H, t, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz)

Example 218

Using (E)-3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-propen-1-oneobtained in Example 217, colorless needle crystalline3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-o-tolyl propan-1-one wasobtained in the same manner as in Example 194.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=7.5, 1.8 Hz), 7.55 (1H, dd, J=8.1, 1.8Hz), 7.51 (1H, d, J=1.8 Hz), 7.43 (1H, br s), 7.36 (1H, td, J=7.5, 1.5Hz), 7.27-7.22 (2H, m), 6.90 (1H, d, J=8.1 Hz), 4.17 (2H, q, J=6.9 Hz),4.14 (2H, q, J=6.9 Hz), 3.32 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),2.49 (3H, s), 1.48 (6H, t, J=6.9 Hz)

Example 219

Using 2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde obtained inReference Example 64, pale yellow powdery(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-propen-1-onewas obtained in the same manner as in Example 193.

¹H-NMR (CDCl₃) δ: 7.81 (1H, s), 7.69-7.26 (13H, m), 6.96 (1H, d, J=9.0Hz), 5.23 (2H, s), 3.94 (3H, s), 2.47 (3H, s)

Example 220

Using(E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolyl-2-propen-1-oneobtained in Example 219, colorless powdery3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolyl propan-1-one wasobtained in the same manner as in Example 194.

¹H-NMR (CDCl₃) δ: 7.67 (1H, dd, J=7.2, 1.8 Hz), 7.56 (1H, d, J=1.8 Hz),7.53 (1H, dd, J=8.1, 1.8 Hz), 7.43 (1H, s), 7.35 (1H, td, J=7.2, 1.8Hz), 7.26-7.22 (2H, m), 6.89 (1H, d, J=8.1 Hz), 5.69 (1H, s), 3.94 (3H,s), 3.31 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.49 (3H, s)

Example 221

A 0.15 g quantity of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-oneobtained in Example 220 was dissolved in 10 ml of isopropyl alcohol. An86 μl quantity of (bromomethyl)cyclopropane and 200 μl of1,8-diazabicyclo[5,4,0]undec-7-ene were added thereto, and the mixturewas heated and refluxed for 24 hours. Water was added to the reactionmixture, and extraction was then performed with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=3:1), and recrystallized from acetone/diisopropyl ether/n-hexaneto give 71 mg of colorless needle crystalline3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one.

¹H-NMR (CDCl₃) δ: 7.68 (1H, dd, J=7.5, 1.5 Hz), 7.57 (1H, dd, J=8.1, 2.1Hz), 7.49 (1H, d, J=2.1 Hz), 7.43 (1H, t, J=0.9 Hz), 7.36 (1H, td,J=7.5, 1.5 Hz), 7.25-7.22 (2H, m), 6.91 (1H, d, J=8.1 Hz), 3.93 (2H, d,J=6.9 Hz), 3.92 (3H, s), 3.32 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),2.49 (3H, s), 1.41-1.32 (1H, m), 0.69-0.63 (2H, m), 0.40-0.35 (2H, m)

Example 222

Using 2-(3-isopropoxy-4-methoxyphenyl)oxazole-4-carbaldehyde obtained inReference Example 69, yellow powdery(E)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-benzyloxyphenyl)-2-propen-1-onewas obtained in the same manner as in Example 193.

¹H-NMR (CDCl₃) δ: 7.76 (1H, s), 7.69-6.92 (14H, m), 5.20 (2H, s), 4.63(1H, sept., J=6.0 Hz), 1.38 (6H, d, J=6.0 Hz)

Example 223

Using(E)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-benzyloxyphenyl)-2-propen-1-oneobtained in Example 222, colorless plate crystalline1-(2-hydroxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained in the same manner as in Example 194.

¹H-NMR (CDCl₃) δ: 12.25 (1H, s), 7.82 (1H, dd, J=8.4, 1.5 Hz), 7.58 (1H,dd, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz), 7.46 (1H, ddd, J=8.4, 7.2,1.5 Hz), 7.45 (1H, s), 6.98 (1H, dd, J=8.4, 1.2 Hz), 6.92 (1H, d, J=8.4Hz), 6.89 (1H, ddd, J=8.4, 7.2, 1.2 Hz), 4.65 (1H, sept., J=6.0 Hz),3.90 (3H, s), 3.44 (2H, t, J=7.5 Hz), 3.03 (2H, t, J=7.5 Hz), 1.40 (6H,d, J=6.0 Hz)

Example 224

A 67 mg quantity of1-(2-hydroxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-oneobtained in Example 223 was dissolved in 5 ml of dimethylformamide. A 31μl quantity of allyl bromide and 73 mg of potassium carbonate were addedthereto, and the mixture was stirred at room temperature overnight. A 50μl quantity of allyl bromide was further added thereto, and the mixturewas stirred at 50° C. for 8 hours, and at room temperature overnight.The reaction mixture was added to water, and extraction was thenperformed with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and the solventwas removed under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate 3:1), and crystallizedfrom n-hexane to give 33 mg of colorless powdery1-(2-allyloxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.57 (1H, dd, J=8.4, 2.1Hz), 7.54 (1H, d, J=2.1 Hz), 7.44 (1H, ddd, J=7.8, 7.5, 1.8 Hz), 7.40(1H, br s), 6.99 (1H, td, J=7.8, 1.2 Hz), 6.94 (1H, br d, J=7.5 Hz),6.91 (1H, d, J=8.4 Hz), 6.08 (1H, ddt, J=17.1, 10.5, 5.4 Hz), 5.42 (1H,ddd, J=17.1, 3.0, 1.5 Hz), 5.29 (1H, ddd, J=10.5, 2.7, 1.5 Hz),4.69-4.61 (3H, m), 3.89 (3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t,J=7.2 Hz), 1.39 (6H, d, J=6.3 Hz)

Example 225

Using 0.3 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-oneobtained in Example 220, 0.15 g of white powdery3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one wasobtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 7.68 (1H, m), 7.57 (1H, dd, J=8.1, 2.1 Hz), 7.51 (1H,d, J=2.1 Hz), 7.44 (1H, d, J=0.9 Hz), 7.36 (1H, m), 7.30-7.20 (3H, m),6.91 (1H, d, J=8.4 Hz), 4.18 (2H, q, J=6.9 Hz), 3.92 (3H, s), 3.35-3.25(2H, m), 3.05-2.95 (2H, m), 2.50 (3H, s), 1.50 (3H, t, J=6.9 Hz)

Example 226

Using 0.3 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-oneobtained in Example 220, 0.1 g of white powdery3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-one wasobtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 7.68 (1H, m), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.52 (1H,d, J=2.1 Hz), 7.43 (1H, s), 7.38 (1H, m), 7.35-7.25 (2H, m), 6.92 (1H,d, J=8.4 Hz), 6.13 (1H, ddd, J=17.1, 10.5, 5.4 Hz), 5.44 (1H, ddd,J=17.1, 2.7, 1.5 Hz), 5.31 (1H, ddd, J=10.5, 2.7, 1.5 Hz), 4.68 (1H, dt,J=5.4, 1.5 Hz), 3.92 (3H, s), 3.32 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2Hz), 2.50 (3H, s)

Example 227

Using 0.2 g of3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-oneobtained in Example 220, 0.1 g of pale yellow oily3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-o-tolylpropan-1-onewas obtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 7.69 (1H, m), 7.60-7.50 (2H, m), 7.50-7.30 (3H, m),7.24 (1H, m), 6.91 (1H, dd, J=5.1, 3.0 Hz), 4.65 (1H, m), 3.90 (3H, s),3.35-3.25 (2H, m), 3.05-2.95 (2H, m), 2.49 (3H, s), 1.40 (6H, d, J=6.0Hz)

Example 228

A 65 mg quantity of sodium hydride was suspended in 5 ml oftetrahydrofuran. A 0.27 g quantity of 1-(2-ethoxyphenyl)ethanone and 0.3g of 2-(3-benzyloxy-4-difluoro methoxyphenyl)-4-chloromethyloxazoleobtained in Reference Example 44 was successively added thereto withice-cooling and stirring, and the mixture was stirred for 3 hours withheating and refluxing. An aqueous saturated ammonium chloride solutionwas added to the reaction mixture with ice-cooling and stirring. Afterstirring for 15 minutes, water was added thereto, and extraction wasperformed with ethyl acetate. The mixture was dried over anhydrousmagnesium sulfate, and the solvent was removed. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to give 75 mg of colorless oily3-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.72-7.69 (2H, m), 7.59 (1H, dd, J=8.1, 1.8 Hz),7.47-7.32 (7H, m), 7.00-6.92 (3H, m), 6.61 (1H, t, J=74.7 Hz), 5.20 (2H,s), 4.15 (2H, q, J=7.2 Hz), 3.43 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2Hz), 1.48 (3H, t, J=7.2 Hz)

Example 229

A 75 mg quantity of3-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-oneobtained in Example 228 was dissolved in 1 ml of ethanol. A 7 mgquantity of 10% palladium-carbon powder was added thereto, and themixture was stirred under a hydrogen atmosphere at room temperature for45 minutes. The catalyst was removed by filtration, the filtrate wasconcentrated, and the obtained residue was purified by silica gel columnchromatography (dichloromethane:ethanol=100:1) to give 32 mg of whitepowdery3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.5, 1.8 Hz), 7.65 (1H, d, J=1.8 Hz),7.56-7.43 (3H, m), 7.16 (1H, d, J=6.0 Hz), 6.98-6.92 (2H, m), 6.57 (1H,t, J=74.7 Hz), 5.57 (1H, s), 4.13 (2H, q, J=7.2 Hz), 3.42 (2H, t, J=7.2Hz), 3.00 (2H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Example 230

A 30 mg quantity of3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-oneobtained in Example 229 was dissolved in 0.5 ml of dimethylformamide. An18 mg quantity of 2-bromopropane and 30 mg of potassium carbonate wereadded thereto, and the mixture was stirred at room temperatureovernight. Water was added to the reaction mixture, and extraction wasperformed with ethyl acetate. Drying was performed with anhydrousmagnesium sulfate, and the solvent was removed. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to give 23 mg of white powdery3-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.61 (1H, d, J=1.8 Hz),7.55 (1H, dd, J=8.4, 1.8 Hz), 7.50-7.38 (2H, m), 7.19 (1H, d, J=8.1 Hz),7.00-6.70 (2H, m), 6.60 (1H, t, J=74.7 Hz), 4.72-4.64 (1H, m), 4.13 (2H,q, J=7.2 Hz), 3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.48 (3H,t, J=7.2 Hz), 1.39 (6H, d, J=6.0 Hz)

Example 231

Using 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyl oxazole obtained inReference Example 5 and 1-(2-methoxymethoxy phenyl)ethanone obtained inReference Example 70, yellow oily3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyphenyl)propan-1-one was obtained in the same manner as in Example 190.

¹H-NMR (CDCl₃) δ: 7.66 (1H, dd, J=7.8, 1.8 Hz), 7.59 (1H, dd, J=7.8, 1.8Hz), 7.51 (1H, br s), 7.49-7.27 (7H, m), 7.17 (1H, br d, J=7.8 Hz), 7.04(1H, td, J=7.5, 1.2 Hz), 6.93 (1H, br d, J=7.8 Hz), 5.25 (2H, s), 5.19(2H, s), 3.92 (3H, s), 3.48 (3H, s), 3.39 (2H, t, J=7.2 Hz), 3.00 (2H,t, J=7.2 Hz)

Example 232

Using3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyphenyl)propan-1-oneobtained in Example 231,3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyphenyl)propan-1-one was obtained in the same manner as in Example 194.

¹H-NMR (CDCl₃) δ: 7.66 (1H, dd, J=7.8, 1.8 Hz), 7.55 (1H, d, J=2.1 Hz),7.53 (1H, dd, J=8.1, 2.1 Hz), 7.41 (1H, s), 7.41 (1H, ddd, J=7.8, 7.5,1.8 Hz), 7.17 (1H, br d, J=7.8 Hz), 7.04 (1H, td, J=7.5, 0.8 Hz), 6.89(1H, d, J=8.1 Hz), 5.64 (1H, s), 5.26 (2H, s), 3.94 (3H, s), 3.49 (3H,s), 3.40 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz)

Example 233

Using3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyphenyl)propan-1-oneobtained in Example 232, colorless oily3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-methoxymethoxyphenyl)propan-1-onewas obtained in the same manner as in Example 102.

¹H-NMR (CDCl₃) δ: 7.66 (1H, dd, J=7.5, 1.8 Hz), 7.57 (1H, dd, J=8.4, 1.8Hz), 7.53 (1H, d, J=1.8 Hz), 7.42 (1H, ddd, J=8.4, 7.5, 1.8 Hz), 7.41(1H, s), 7.17 (1H, dd, J=8.4, 1.2 Hz), 7.04 (1H, td, J=7.5, 1.2 Hz),6.91 (1H, d, J=8.4 Hz), 5.26 (2H, s), 4.64 (1H, sept, J=6.0 Hz), 3.90(3H, s), 3.49 (3H, s), 3.40 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),1.39 (6H, d, J=6.0 Hz)

Example 234

Using 0.76 g of 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazoleobtained in Reference Example 58, 60 mg of white powdery3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2,2-trifluoroethoxy)phenyl]propan-1-onewas obtained in the same manner as in Example 228.

¹H-NMR (CDCl₃) δ: 7.76 (1H, dd, J=7.8, 2.1 Hz), 7.58-7.48 (3H, m), 7.39(1H, s), 7.12 (1H, t, J=7.5 Hz), 6.92-6.88 (2H, m), 4.46 (2H, q, J=7.8Hz), 4.18 (2H, q, J=7.2 Hz), 3.92 (3H, s), 3.40 (2H, t, J=7.5 Hz), 3.00(2H, t, J=7.5 Hz), 1.49 (3H, t, J=7.2 Hz)

Example 235

Using 0.76 g of 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazoleobtained in Reference Example 58 and 0.58 g of1-(2-trifluoromethoxyphenyl)ethanone, 0.18 g of pale yellow oily3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-trifluoromethoxyphenyl)propan-1-one was obtained in the same manner as in Example228.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.5, 1.8 Hz), 7.58-7.50 (3H, m), 7.42(1H, s), 7.38-7.30 (2H, m), 6.91 (1H, d, J=8.4 Hz), 4.17 (2H, q, J=6.6Hz), 3.91 (3H, s), 3.45 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 1.49(3H, t, J=6.6 Hz)

Example 236

Using 0.5 g of 3-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]propionic acidobtained in Reference Example 71, 0.32 g of white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-yl-propan-1-one wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 7.55 (1H, dd, J=6.75, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz),7.44 (1H, s), 6.91 (1H, d, J=8.1 Hz), 4.20-4.10 (4H, m), 3.50-3.40 (4H,m), 3.00-2.90 (2H, m), 2.70-2.60 (2H, m), 1.95-1.75 (4H, m), 1.48 (3H,t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Example 237

Using 0.3 g of 3-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]propionic acidobtained in Reference Example 71, 0.28 g of white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-hydroxypyrrolidin-1-yl)propan-1-one was obtained in the same manner as inExample 1.

¹H-NMR (CDCl₃) δ: 7.55 (1H, dd, J=6.75, 1.8 Hz), 7.52 (1H, d, J=1.8 Hz),7.44 (1H, s), 6.91 (1H, d, J=8.1 Hz), 4.20-4.10 (4H, m), 3.50-3.40 (4H,m), 3.00-2.90 (2H, m), 2.70-2.60 (2H, m), 2.10-1.90 (3H, m), 1.48 (3H,t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)

Example 238

Using 1 g of 3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]propionicacid obtained in Reference Example 73, 1.03 g of pale yellow powdery3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-ylpropan-1-onewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 7.61-7.27 (8H, m), 6.93 (1H, d, J=8.4 Hz), 5.20 (2H,s), 3.97 (3H, s), 3.49-3.39 (4H, m), 2.94 (2H, t, J=7.5 Hz), 2.65 (2H,t, J=7.5 Hz), 1.95-1.78 (4H, m)

Example 239

Using 1 g of3-[2-(4-benzyloxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-yl-propan-1-oneobtained in Example 238, 0.59 g of white powdery3-[2-(4-hydroxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-ylpropan-1-onewas obtained in the same manner as in Example 2.

¹H-NMR (CDCl₃) δ: 7.56-7.51 (2H, m), 7.44 (1H, s), 6.90 (1H, d, J=8.4Hz), 5.97 (1H, s), 3.97 (3H, s), 3.49-3.39 (4H, m), 2.94 (2H, t, J=7.5Hz), 2.66 (2H, t, J=7.5 Hz), 1.97-1.79 (4H, m)

Example 240

Using 0.15 g of3-[2-(4-hydroxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-yl-propan-1-oneobtained in Example 239, 0.13 g of white powdery3-[2-(4-ethoxy-3-methoxyphenyl)oxazol-4-yl]-1-pyrrolidin-1-ylpropan-1-onewas obtained in the same manner as in Example 3.

¹H-NMR (CDCl₃) δ: 7.57 (1H, dd, J=8.1, 2.1 Hz), 7.52 (1H, d, J=1.8 Hz),7.45 (1H, s), 6.91 (1H, d, J=8.1 Hz), 4.15 (2H, q, J=6.9 Hz), 3.96 (3H,s), 3.49-3.40 (4H, m), 2.94 (2H, t, J=7.2 Hz), 2.66 (2H, t, J=7.2 Hz),1.97-1.79 (4H, m), 1.49 (3H, t, J=6.9 Hz)

Example 241

N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamideobtained in Example 25 was dissolved in 1 ml of dimethylformamide. A 30mg quantity of sodium hydride was added thereto with ice-cooling andstirring, and the mixture was stirred for 30 minutes. A 30 mg quantityof methyl iodide was added thereto, and the reaction mixture was stirredat room temperature for 2 hours. Water and ethyl acetate were then addedthereto, and extraction was performed. The organic layer was washed withwater twice and concentrated by removing the solvent under reducedpressure. The residue was purified by silica gel chromatography(n-hexane:ethyl acetate=3:1) to give 35 mg of colorless oilyN-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-N-methyl-2-trifluoromethylbenzamide.

¹H-NMR (CDCl₃) δ: 7.72-7.34 (7H, m), 6.94 (1H, dd, J=8.4, 1.8 Hz),4.88-4.11 (1H, m), 3.98-3.89 (5H, m), 3.17-2.88 (3H, m), 1.43-1.34 (1H,m), 0.71-0.64 (2H, m), 0.42-0.36 (2H, m)

Example 242

Using 0.14 g of [2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]methylamineobtained in Reference Example 74, 70 mg of colorless oilyN-[2-(3,4-dimethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-N-methylbenzamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 7.60-7.26 (5H, m), 7.00-6.87 (3H, m), 4.23-4.02 (8H,m), 3.19-2.96 (3H, m), 1.52-1.40 (6H, m), 1.36 (3H, t, J=6.9 Hz)

Example 243

Using 0.2 g of 2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]ethylamine obtainedin Reference Example 78 and 0.18 g of 2-ethoxy benzoic acid, 0.14 g ofwhite powderyN-{2-[2-(3,4-dimethoxyphenyl)oxazol-4-yl]ethyl}-2-ethoxybenzamide wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.22 (1H, dd, J=7.5, 4.8 Hz), 7.60-7.50 (2H, m), 7.47(1H, s), 7.39 (1H, m), 7.06 (1H, m), 6.95-6.85 (2H, m), 4.30-4.05 (6H,m), 4.09 (2H, q, J=6.9 Hz), 3.85 (2H, q, J=6.6 Hz), 2.91 (2H, t, J=6.6Hz), 1.48 (6H, t, J=6.9 Hz), 1.28 (6H, t, J=6.9 Hz)

Example 244

Using 0.3 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid obtainedin Reference Example 80 and 0.28 g of 1-(2-amino)ethanone, 0.32 g ofwhite powderyN-(2-oxo-2-phenylethyl)-2-(3,4-diethoxyphenyl)oxazole-4-carboxamide wasobtained in the same manner as in Example 1.

¹H-NMR (DMSO-d₆) δ: 8.67 (1H, d, J=0.9 Hz), 8.49 (1H, t, J=5.7 Hz),8.10-8.00 (2H, m), 7.70-7.50 (5H, m), 7.16 (1H, m), 4.81 (2H, d, J=5.7Hz), 4.13 (4H, q, J=6.9 Hz), 1.38 (6H, t, J=6.9 Hz), 1.37 (3H, t, J=6.9Hz)

Example 245

Using 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid obtained inReference Example 80, 0.32 g of white powdery1-(4-{4-[2-(3,4-diethoxyphenyl)oxazole-4-carbonyl]piperazin-1-yl}phenyl)ethanonewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.20 (1H, s), 7.95-7.85 (2H, m), 7.62 (1H, dd, J=8.4,2.1 Hz), 7.54 (1H, d, J=2.1 Hz), 7.00-6.85 (3H, m), 4.40-4.20 (2H, m),4.19 (2H, q, J=6.9 Hz), 4.16 (2H, q, J=6.9 Hz), 4.00-3.80 (2H, m),3.50-3.45 (4H, m), 2.53 (3H, s), 1.50 (3H, t, J=6.9 Hz), 1.50 (3H, t,J=6.9 Hz)

Example 246

Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid obtainedin Reference Example 80 and 0.2 g of 1-(4-methoxyphenyl)piperazine, 0.36g of white powdery4-(2-(3,4-diethoxyphenyl)oxazol-4-yl)-1-(4-methoxyphenyl)piperazine wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.16 (1H, s), 7.61 (1H, dd, J=8.7, 2.1 Hz), 7.54 (1H,s), 6.95-6.84 (5H, m), 4.40-4.30 (2H, m), 4.21-4.12 (4H, m), 4.00-3.93(2H, m), 3.78 (3H, s), 3.14 (4H, t, J=4.8 Hz), 1.47 (6H, t, J=7.2 Hz)

Example 247

Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid obtainedin Reference Example 80 and 1-(4-hydroxyphenyl)piperazine, white powdery4-(2-(3,4-diethoxyphenyl)oxazol-4-yl)-1-(4-hydroxyphenyl)piperazine wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.16 (1H, s), 7.61 (1H, dd, J=8.7, 2.1 Hz), 7.54 (1H,s), 6.95-6.78 (5H, m), 4.40-4.30 (2H, m), 4.21-4.12 (4H, m), 4.00-3.93(2H, m), 3.14 (4H, t, J=4.8 Hz), 1.49 (6H, t, J=7.2 Hz)

Example 248

Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid obtainedin Reference Example 80 and 0.14 g of 2-phenylethylamine, 0.21 g ofwhite powdery N-phenethyl-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.17 (1H, s), 7.56 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H,d, J=2.1 Hz), 7.36-7.21 (5H, m), 7.12 (1H, br s), 6.93 (1H, d, J=8.4Hz), 4.22-4.12 (4H, m), 3.74-3.66 (2H, m), 2.95 (2H, t, J=7.2 Hz),1.57-1.46 (6H, m)

Example 249

Using 0.28 g of 2-(3,4-diethoxyphenyl)oxazole-4-carboxylic acid obtainedin Reference Example 80 and 0.13 g of 1-(2-aminoethyl)pyrrolidine, 0.15g of pale yellow powderyN-(2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dimethoxyphenyl)oxazole-4-carboxamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.17 (1H, s), 7.60 (1H, dd, J=8.4, 1.8 Hz), 7.55 (1H,d, J=1.8 Hz), 7.44 (1H, br s), 6.92 (1H, d, J=8.4 Hz), 4.23-4.12 (4H,m), 3.65-3.58 (2H, m), 2.79 (2H, t, J=6.6 Hz), 2.70-2.58 (4H, m),1.87-1.75 (4H, m), 1.53-1.46 (6H, m)

Example 250

Using 0.15 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]acetic acid obtainedin Reference Example 81 and 0.11 g of o-phenetidine, 0.12 g of whitepowdery2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-N-(2-ethoxyphenyl)acetamide wasobtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 8.74 (1H, br s), 8.37 (1H, dd, J=7.2, 1.8 Hz),7.70-7.65 (2H, m), 7.61 (1H, d, J=1.8 Hz), 7.00-6.90 (3H, m), 6.80 (1H,dd, J=7.8, 1.2 Hz), 4.18 (2H, q, J=6.9 Hz), 4.16 (2H, q, J=6.9 Hz), 3.97(2H, q, J=7.2 Hz), 3.74 (2H, s), 1.49 (3H, t, J=6.9 Hz), 1.49 (3H, t,J=6.9 Hz), 1.18 (3H, t, J=7.2 Hz)

Example 251

Using 0.15 g of [2-(3,4-diethoxyphenyl)oxazol-4-yl]acetic acid obtainedin Reference Example 81 and 85 mg of 2-amino-3-hydroxypyridine, 0.11 gof white powdery2-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-N-(3-hydroxypyridin-2-yl)acetamidewas obtained in the same manner as in Example 1.

¹H-NMR (CDCl₃) δ: 10.37 (1H, brs), 9.88 (1H, brs), 7.84 (1H, dd, J=4.8,1.2 Hz), 7.65-7.60 (3H, m), 7.31 (1H, dd, J=4.2, 1.2 Hz), 6.94 (1H, d,J=9.0 Hz), 4.22 (2H, q, J=6.9 Hz), 4.16 (2H, q, J=6.9 Hz), 1.51 (3H, t,J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz)

Example 252

A 0.5 g quantity of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazoleobtained in Reference Example 35, 0.36 g of piperazin-2-one and 0.28 gof potassium carbonate were added to 10 ml of acetonitrile, and themixture was heated and refluxed for 7 hours. The residue was dilutedwith ethyl acetate, and washed with water and then with saturated brine.The organic layer was dried over anhydrous magnesium sulfate andconcentrated by removing the solvent under reduced pressure. The residuewas purified by silica gel column chromatography(dichloromethane:methanol=1:0 to 50:1), and the obtained crude crystalswere recrystallized from ethyl acetate to give 0.25 g of colorlesscrystalline 4-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]piperazin-2-one.

¹H-NMR (CDCl₃) δ: 7.59 (1H, d, J=8.1, 2.1 Hz), 7.56 (1H, d, J=2.1 Hz),6.91 (1H, d, J=8.1 Hz), 6.03 (1H, brs), 4.17 (2H, q, J=6.9 Hz), 4.15(2H, q, J=6.9 Hz), 3.61 (2H, s), 3.45-3.35 (2H, m), 3.27 (2H, s),2.80-2.75 (2H, m), 1.48 (6H, t, J=6.9 Hz)

Example 253

Using 0.5 g of 4-chloromethyl-2-(3,4-diethoxyphenyl)oxazole obtained inReference Example 35 and 0.5 g of morpholine, 0.31 g of white powdery4-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]morpholine was obtained inthe same manner as in Example 252.

¹H-NMR (CDCl₃) δ: 7.70-7.50 (2H, m), 7.54 (1H, s), 6.91 (1H, d, J=8.4Hz), 4.25-4.10 (4H, m), 3.80-3.70 (4H, m), 3.51 (2H, s), 2.60-2.50 (4H,m), 1.48 (6H, t, J=6.9 Hz)

Example 254

A 0.5 g quantity of 4-chloromethyl-2-(3,4-diethoxy phenyl)oxazoleobtained in Reference Example 35, 0.28 g of 2-mercaptopyridine and 0.28g of potassium carbonate were added to 10 ml of dimethylformamide, andthe mixture was stirred at room temperature for 24 hours. The reactionmixture was diluted with ethyl acetate, and washed with water and thenwith saturated brine. The organic layer was dried over anhydrousmagnesium sulfate and concentrated by removing the solvent under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:4 to 1:2), and the obtained crude crystalswere recrystallized from a mixture of ethyl acetate and n-hexane to give0.63 g of colorless crystalline2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethylsulfanyl]pyridine.

¹H-NMR (CDCl₃) δ: 8.45 (3H, m), 7.60-7.50 (3H, m), 7.47 (1H, m), 7.18(1H, d, J=8.1 Hz), 6.99 (1H, m), 6.89 (1H, d, J=8.1 Hz), 4.38 (2H, s),4.17 (2H, q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 1.47 (6H, t, J=6.9 Hz)

Example 255

A 0.58 g quantity of2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethylsulfanyl]pyridine obtained inExample 254 was added to 20 ml of dichloromethane. A 0.55 g quantity ofm-chloroperbenzoic acid was gradually added thereto with ice-cooling,and the mixture was then stirred. The reaction mixture was diluted with30 ml of dichloromethane, and washed with an aqueous 10% sodiumhydroxide solution and then with saturated brine. The organic layer wasdried over anhydrous magnesium sulfate and concentrated by removing thesolvent under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate:n-hexane=2:1 to 3:1), and theobtained crude crystals was recrystallized from a mixture of ethylacetate and n-hexane to give 0.49 g of colorless crystalline2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethanesulfonyl]pyridine.

¹H-NMR (CDCl₃) δ: 8.81 (1H, m), 8.00 (1H, m), 7.91 (1H, m), 7.61 (1H,s), 7.55 (1H, m), 7.50-7.40 (2H, m), 6.87 (1H, d, J=8.4 Hz), 4.71 (2H,s), 4.13 (4H, q, J=6.9 Hz), 1.47 (6H, t, J=6.9 Hz)

Example 256

A 0.27 g quantity of [2-(3,4-diethoxyphenyl)oxazol-4-yl]methylamineobtained in Reference Example 37 and 0.3 ml of triethylamine weredissolved in 10 ml of acetonitrile. A 0.19 g quantity ofo-toluenesulfonylchloride was added thereto, and the mixture was stirredat room temperature for 1 hour. Water was added to the reaction mixture,and extraction was performed with ethyl acetate. The organic layer waswashed with water twice, and the solvent was removed. The obtainedresidue was purified using a silica gel column (n-hexane:ethylacetate=1:1). The obtained crude crystals were recrystallized from amixture of n-hexane and ethyl acetate to give 0.3 g of white powderyN-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-2-methylbenzenesulfonamide.

¹H-NMR (CDCl₃) δ: 7.96 (1H, dd, J=7.5, 1.5 Hz), 7.48-7.16 (6H, m), 6.90(1H, d, J=8.4 Hz), 5.11 (1H, br s), 4.21-4.11 (6H, m), 2.64 (3H, s),1.52-1.46 (6H, m)

Example 257

A 0.5 g quantity of3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-oneobtained in Example 102 and 0.18 ml of hydrazine monohydrate were addedto diethylene glycol. A 0.14 g quantity of potassium hydroxide was addedthereto, and the mixture was stirred at 150° C. for 1 hour. The reactionmixture was allowed to cool, water was then added thereto, andextraction was performed with ethyl acetate. Drying was performed withanhydrous magnesium sulfate, and the solvent was removed. The residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to give 0.1 g of colorless oily2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-[3-(2-ethoxyphenyl)propyl]oxazole.

¹H-NMR (CDCl₃) δ: 7.58 (1H, dd, J=8.4, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz),7.39 (1H, s), 7.17-7.12 (2H, m), 6.93-6.81 (3H, m), 4.03 (2H, q, J=6.9Hz), 3.94-3.92 (5H, m), 2.72 (2H, t, J=7.5 Hz), 2.62 (2H, t, J=7.5 Hz),2.03-1.96 (2H, m), 1.43-1.25 (4H, m), 0.69-0.63 (2H, m), 0.40-0.35 (2H,m)

Example 258

A 1.6 g quantity of sodium hydride was suspended in 100 ml oftetrahydrofuran. A 2.68 g quantity of 1-(2-methylphenyl)ethanone and6.58 g of 2-(3-benzyloxy-4-methoxyphenyl)-4-chloro methyloxazoleobtained in Reference Example 5 were successively added thereto withice-cooling and stirring, and the mixture was heated and refluxed for 4hours. An aqueous saturated ammonium chloride solution was added theretowith ice-cooling. After stirring for 15 minutes, water was addedthereto, and extraction was performed with ethyl acetate. Drying wasthen performed with anhydrous magnesium sulfate, and the solvent wasremoved. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1), and 1.6 g of the obtained crude productwas dissolved in 20 ml of ethanol. A 0.16 g quantity of 10%palladium-carbon powder was added thereto, and the mixture was stirredunder a hydrogen atmosphere for 18 hours. The reaction mixture wasfiltered, and the obtained filtrate was concentrated. The residue waspurified by silica gel column chromatography(dichloromethane:ethanol=100:1) to give 0.47 g of yellow oily2-(3-hydroxy-4-methoxyphenyl)-4-(3-o-tolyl propyl)oxazole.

¹H-NMR (CDCl₃) δ: 7.60-7.54 (2H, m), 7.38 (1H, s), 7.15-7.08 (4H, m),6.90 (1H, d, J=8.4 Hz), 5.65 (1H, s), 3.94 (3H, s), 2.72-2.62 (4H, m),2.37 (3H, s)

Example 259

Using 0.47 g of 2-(3-hydroxy-4-methoxyphenyl)-4-(3-o-tolylpropyl)oxazoleobtained in Example 258, 0.37 g of colorless oily2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-(3-o-tolylpropyl)oxazole wasobtained in the same manner as in Example 111.

¹H-NMR (CDCl₃) δ: 7.58 (1H, dd, J=8.1, 2.1 Hz), 7.51 (1H, d, J=2.1 Hz),7.38 (1H, s), 7.15-7.08 (4H, m), 6.92 (1H, d, J=8.1 Hz), 3.94-3.92 (5H,m), 2.72-2.62 (4H, m), 2.31 (3H, s), 2.04-1.92 (2H, m), 1.40-1.35 (1H,m), 0.69-0.63 (2H, m), 0.40-0.35 (2H, m)

Example 260

A 0.21 g quantity of3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-oneobtained in Example 102 was added to 5 ml of ethanol, and the mixturewas stirred with ice-cooling. A 37 mg quantity of sodium borohydride wasgradually added thereto. After the temperature of the reaction mixturehad reached room temperature, stirring was performed for 2 hours. Anaqueous 5N hydrochloric acid solution was added to the reaction mixture,and solvent was then removed. Extraction was performed withdichloromethane, and the extract was washed with saturate brine. Theextract was then dried over anhydrous magnesium sulfate, the solvent wasremoved, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to give 0.18 g of colorlessoily3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-ol.

¹H-NMR (CDCl₃) δ: 7.58 (1H, dd, J=8.4, 2.1 Hz), 7.50 (1H, d, J=1.8 Hz),7.39-7.35 (2H, m), 7.23-7.18 (1H, m), 6.97-6.84 (3H, m), 5.00 (1H, brs), 4.07 (2H, q, J=6.6 Hz), 3.94-3.92 (5H, m), 3.44 (1H, br s),2.80-2.60 (2H, m), 2.20-2.15 (2H, m), 1.43-1.37 (4H, m), 0.69-0.63 (2H,m), 0.40-0.37 (2H, m)

Example 261

An 80 mg quantity of 3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained inExample 139 was dissolved in 3 ml of dimethylformamide. A 0.2 g quantityof sodium hydride was added thereto with ice-cooling and stirring, andthe mixture was stirred for 30 minutes. A 75 mg quantity of methyliodide was added thereto, and the reaction mixture was stirred at roomtemperature for 8 hours. Water was added to the reaction mixture, andextraction was performed with ethyl acetate. The organic layer waswashed with water twice, and the solvent was removed. The obtainedresidue was purified using a silica gel column (n-hexane:ethylacetate=3:1) to give 35 mg of colorless oily3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-2,2-dimethyl-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.41 (1H, dd, J=4.5, 1.2 Hz), 7.38-7.60 (3H, m), 7.34(1H, s), 7.21-7.24 (1H, m), 6.90 (1H, d, J=8.7 Hz), 4.63 (1H, sept.,J=6.0 Hz), 3.94 (3H, s), 3.15 (2H, s), 2.28 (3H, s), 1.38-1.49 (12H, m)

Example 262

Using 0.9 g of methyl3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}propionateobtained in Reference Example 83, 1.05 g of yellow oily methyl3-(3-methoxypyridin-2-yl)-2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-oxopropinatewas obtained in the same manner as in Example 100.

¹H-NMR (CDCl₃) δ: 8.25 (1H, dd, J=4.5, 1.5 Hz), 7.65 (1H, dd, J=8.4, 2.1Hz), 7.55 (1H, d, J=2.1 Hz), 7.47-7.33 (3H, m), 6.94 (1H, d, J=8.4 Hz),5.17 (1H, t, J=6.9 Hz), 4.43 (2H, q, J=8.4 Hz), 3.93 (3H, s), 3.92 (3H,s), 3.65 (3H, s), 3.32-3.23 (2H, m)

Example 263

Using 0.7 g of methyl3-(3-methoxypyridin-2-yl)-2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-oxopropionateobtained in Example 262, 0.42 g of colorless oily methyl2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-methyl-3-(3-methylpyridin-2-yl)-3-oxopropinatewas obtained in the same manner as in Example 261.

¹H-NMR (CDCl₃) δ: 8.18 (1H, dd, J=6.9, 1.8 Hz), 7.64 (1H, dd, J=8.4, 2.1Hz), 7.54 (1H, d, J=2.1 Hz), 7.42-7.34 (3H, m), 6.93 (1H, d, J=8.7 Hz),4.43 (2H, q, J=8.4 Hz), 3.93 (3H, s), 3.91 (3H, s), 3.64 (3H, s), 3.40(1H, d, J=15 Hz), 3.26 (1H, d, J=15 Hz)

Example 264

Using 0.42 g of methyl2-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-methyl-3-(3-methylpyridin-2-yl)-3-oxopropinate obtained in Example 263, 0.25 g ofcolorless oily1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-2-methylpropan-1-onewas obtained in the same manner as in Example 136.

¹H-NMR (CDCl₃) δ: 8.24 (1H, dd, J=4.5, 1.5 Hz), 7.67 (1H, dd, J=8.4, 2.1Hz), 7.57 (1H, d, J=2.1 Hz), 7.43-7.28 (3H, m), 6.94 (1H, d, J=8.7 Hz),4.45 (1H, q, J=8.4 Hz), 4.21 (1H, q, J=6.9 Hz), 3.91 (3H, s), 3.88 (3H,s), 3.15-3.06 (1H, m), 2.73-2.64 (1H, m), 1.23 (3H, d, J=7.2 Hz)

Example 265

Using 0.2 g of1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-y}-2-methylpropan-1-one obtained in Example 264, 80 mg of colorless oily1-(3-methoxypyridin-2-yl)-3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-2,2-dimethylpropan-1-onewas obtained in the same manner as in Example 261.

¹H-NMR (CDCl₃) δ: 8.17 (1H, dd, J=4.5, 1.5 Hz), 7.70 (1H, dd, J=8.4, 1.8Hz), 7.60 (1H, d, J=1.8 Hz), 7.31-7.21 (2H, m), 6.96 (1H, d, J=8.4 Hz),4.45 (2H, q, J=8.4 Hz), 3.92 (3H, s), 3.78 (3H, s), 3.05 (2H, s), 1.34(6H, s)

Example 266

A 60 ml quantity of trifluoroacetic acid was stirred with ice cooling,12.3 g of the compound obtained in Example 231 was added thereto, andstirring was conducted for one hour. At the completion of the reaction,the reaction mixture was neutralized by addition of an aqueous saturatedsodium bicarbonate solution, and ethyl acetate was added to the obtainedmixture. The organic layer was washed twice with water, separated,concentrated under reduced pressure, and the obtained crude crystalswere recrystallized from ethanol, thereby yielding 5.9 g of whitepowdery3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 12.2 (1H, s), 7.81 (1H, d, J=8.1 Hz), 7.62-7.26 (9H,m), 6.99-6.85 (3H, m), 5.19 (2H, s), 3.92 (3H, s), 3.43 (2H, t, J=7.5Hz), 3.02 (2H, t, J=7.5 Hz)

Example 267

Using the compound obtained in Example 266 and chlorodifluoromethane,white powdery 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-difluoromethoxyphenyl)propan-1-one was obtainedfollowing the procedure of Example 19.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.90-6.60 (7H, m), 6.34(1H, t, J=73.8 Hz), 5.20 (2H, s), 3.92 (3H, s), 3.36 (2H, t, J=7.2 Hz),2.29 (2H, t, J=7.2 Hz)

Reference Example 84

Using 2-fluoroethanol, a colorless oily 2-fluoroethyl methanesulfonatewas obtained following the procedure of Reference Example 50.

¹H-NMR (CDCl₃) δ: 4.76-4.73 (1H, m), 4.60-4.58 (1H, m), 4.53-4.50 (1H,m), 4.43-4.41 (1H, m), 3.08 (3H, s)

Reference Example 85

Using 2,2-difluoroethanol, colorless oily 2,2-difluoroethylmethanesulfonate was obtained following the procedure of ReferenceExample 50.

¹H-NMR (CDCl₃) δ: 6.01 (1H, tt, J=54.3, 3.9 Hz), 4.38 (2H, td, J=12.9,3.9 Hz), 3.12 (3H, s)

Example 268

Using the compound obtained in Example 266 and the compound obtained inReference Example 84, white powdery3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.8 Hz), 7.61-7.59 (2H, m),7.49-7.31 (7H, m), 7.07 (1H, t, J=7.8 Hz), 6.92 (2H, d, J=8.7 Hz), 5.20(2H, s), 4.90-4.87 (1H, m), 4.74-4.71 (1H, m), 4.37-4.35 (1H, m),4.28-4.26 (1H, m), 3.92 (3H, s), 3.44 (2H, t, J=7.5 Hz), 2.99 (2H, t,J=7.5 Hz)

Example 269

Using the compound obtained in Example 266 and the compound obtained inReference Example 85, white powdery3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.8 Hz), 7.61-7.28 (9H, m), 7.08(1H, t, J=7.8 Hz), 6.95-6.89 (2H, m), 6.22 (1H, tt, J=54.9, 3.9 Hz),5.19 (2H, s), 4.29 (1H, td, J=12.9, 3.9 Hz), 3.92 (3H, s), 3.38 (2H, t,J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz)

Example 270

Using the compound obtained in Example 267, white powdery1-(2-difluoromethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure ofExample 2.

¹H-NMR (CDCl₃) δ: 7.71 (1H, t, J=7.5 Hz), 7.54-7.41 (4H, m), 7.38-7.16(2H, m), 6.89 (1H, d, J=8.1 Hz), 6.59 (1H, t, J=74.7 Hz), 5.69 (1H, s),3.93 (3H, s), 3.36 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz)

Example 271

Using the compound obtained in Example 268, white powdery1-[2-(2-fluoroethoxy)phenyl]-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure ofExample 2.

¹H-NMR (CDCl₃) δ: 7.73 (1H, dd, J=7.8, 1.8 Hz), 7.55-7.42 (4H, m), 7.05(1H, t, J=7.8 Hz), 6.91 (2H, d, J=8.7 Hz), 4.91-4.88 (1H, m), 4.75-4.72(1H, m), 4.38-4.35 (1H, m), 4.29-4.26 (1H, m), 3.94 (3H, s), 3.43 (2H,t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz)

Example 272

Using the compound obtained in Example 269, white powdery1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 2.

¹H-NMR (CDCl₃) δ: 7.73 (1H, dd, J=7.8, 1.8 Hz), 7.56-7.41 (4H, m), 7.08(1H, t, J=7.8 Hz), 6.92-6.87 (2H, m), 6.21 (1H, tt, J=54.9, 3.9 Hz),5.67 (1H, s), 4.29 (1H, td, J=12.9, 3.9 Hz), 3.94 (3H, s), 3.38 (2H, t,J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz)

Example 273

Using the compound obtained in Example 270 and 2-bromopropane, whitepowdery1-(2-difluoromethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.70-7.25 (5H, m), 7.20-6.80 (2H, m), 6.59 (1H, t.,J=73.5 Hz), 4.64 (1H, m), 3.93 (3H, s), 1.39 (3H, d, J=6.0 Hz)

Example 274

Using the compound obtained in Example 270 and ethyl iodide, whitepowdery1-(2-difluoromethoxyphenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.60-7.46 (3H, m), 7.42(1H, s), 7.31-7.16 (2H, m), 6.91 (1H, d, J=8.1 Hz), 6.59 (1H, t, J=73.5Hz), 4.18 (2H, q, J=7.2 Hz), 3.92 (3H, s), 3.37 (2H, t, J=7.2 Hz), 3.00(2H, t, J=7.2 Hz), 1.49 (3H, t, J=7.2 Hz)

Example 275

Using the compound obtained in Example 271 and 2-bromopropane, whitepowdery1-(2-fluoroethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.73 (1H, d, J=7.2 Hz), 7.58-7.54 (2H, m), 7.45-7.41(2H, m), 7.04 (1H, t, J=7.2 Hz), 6.92 (2H, t, J=8.1 Hz), 4.81 (2H, dt,J=47.4, 4.2 Hz), 4.64-4.60 (1H, m), 4.32 (2H, dt, J=23.1, 4.2 Hz), 3.89(3H, s), 3.43 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.39 (6H, d,J=5.7 Hz)

Example 276

Using the compound obtained in Example 271 and 4-bromo-1-butene, whitepowdery3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.73 (1H, d, J=7.5 Hz), 7.58-7.53 (2H, m), 7.45-7.42(2H, m), 7.03 (1H, t, J=7.8 Hz), 6.92 (2H, t, J=8.4 Hz), 6.00-5.84 (1H,m), 5.21-5.09 (2H, m) 4.81 (2H, dt, J=47.4, 4.2 Hz), 4.32 (2H, dt,J=23.1, 4.2 Hz), 4.14 (2H, t, J=7.2 Hz), 3.90 (3H, s), 3.43 (2H, t,J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.64-2.61 (2H, m)

Example 277

Using the compound obtained in Example 271 and isobutyl bromide, whitepowdery1-[2-(2-fluoroethoxy)phenyl]-3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.73 (1H, dd, J=7.8, 18 Hz), 7.57-7.51 (2H, m),7.48-7.42 (2H, m), 7.40 (1H, t, J=7.5 Hz), 6.92 (2H, t, J=8.7 Hz), 4.81(2H, dt, J=47.4, 4.2 Hz), 4.32 (2H, dt, J=23.1, 4.2 Hz), 3.90 (3H, s),3.84 (2H, d, J=6.9 Hz), 3.43 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz),2.23-2.14 (1H, m), 1.04 (6H, d, J=5.7 Hz)

Example 278

Using the compound obtained in Example 272 and 2-bromopropane, whitepowdery1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.5, 1.8 Hz), 7.59-7.44 (3H, m), 7.41(1H, s), 7.08 (1H, t, J=7.5 Hz), 6.91 (1H, d, J=8.4 Hz), 6.22 (1H, tt,J=54.6, 3.9 Hz) 4.65 (1H, sept., J=6.0 Hz), 4.29 (2H, td, J=12.9, 3.9Hz), 3.90 (3H, s) 3.38 (2H, t, J=7.5 Hz) 2.99 (2H, t, J=7.5 Hz) 1.40(6H, d, J=6.0 Hz)

Example 279

Using the compound obtained in Example 272 and 1-bromopropane, whitepowdery1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-propoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.8 Hz), 7.61-7.43 (3H, m), 7.41(1H, s), 7.08 (1H, t, J=7.5 Hz), 6.92-6.89 (2H, m), 6.23 (1H, tt,J=54.6, 3.9 Hz), 4.29 (2H, td, J=12.9, 3.9 Hz), 4.06 (2H, t, J=6.9 Hz),3.91 (3H, s), 3.38 (2H, t, J=1.5 Hz), 2.99 (2H, t, J=7.5 Hz), 1.90 (2H,qt, J=7.2 Hz), 1.06 (3H, t, J=7.2 Hz)

Example 280

Using the compound obtained in Example 272 and ethyl iodide, whitepowdery1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.8 Hz), 7.61-7.44 (3H, m), 7.41(1H, s), 7.08 (1H, t, J=7.8 Hz), 6.93-6.90 (2H, m), 6.23 (1H, tt,J=54.6, 3.9 Hz) 4.29 (2H, td, J=12.9, 3.9 Hz), 4.18 (2H, q, J=6.9 Hz),3.92 (3H, s), 3.38 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 1.50 (3H,t, J=6.9 Hz)

Example 281

Using the compound obtained in Example 272 and ally bromide, whitepowdery3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.8 Hz), 7.60-7.44 (3H, m), 7.41(1H, s), 7.08 (1H, t, J=7.5 Hz), 6.94-6.89 (2H, m), 6.41-6.04 (2H, m),5.44 (1H, dd, J=17.4, 1.5 Hz), 5.31 (1H, dd, J=10.2, 1.5 Hz), 4.29 (2H,td, J=12.9, 3.9 Hz), 3.92 (3H, s), 3.38 (2H, t, J=7.2 Hz), 2.99 (2H, t,J=7.2 Hz)

Example 282

Using the compound obtained in Example 272 and 4-bromo-1-butene, whitepowdery3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.75 (1H, dd, J=7.8, 1.8 Hz), 7.60-7.44 (3H, m), 7.42(1H, s), 7.09 (1H, t, J=7.5 Hz), 6.93-6.89 (2H, m), 6.23 (1H, tt,J=54.6, 3.9 Hz), 5.99-5.85 (1H, m), 5.23-5.10 (2H, m), 4.29 (2H, td,J=12.9, 3.9 Hz), 4.14 (2H, t, J=7.2 Hz), 3.91 (3H, s), 3.39 (2H, t,J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.68-2.60 (2H, m)

Example 283

Using the compound obtained in Example 272 and(bromomethyl)cyclopropane, white powdery 3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.75 (1H, dd, J=7.8, 1.8 Hz), 7.58-7.44 (3H, m), 7.41(1H, s), 7.09 (1H, t, J=7.5 Hz), 6.93-6.90 (2H, m), 6.24 (1H, tt,J=54.6, 3.9 Hz), 4.29 (2H, td, J=12.9, 3.9 Hz), 3.94-3.91 (5H, m), 3.39(2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.43-1.33 (1H, m), 0.70-0.63(2H, m), 0.41-0.35 (2H, m)

Example 284

Using the compound obtained in Example 272 and the compound obtained inReference Example 85, white powdery3-{2-[3-(2,2-difluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.8 Hz), 7.65 (1H, dd, J=7.8, 1.8Hz), 7.50 (1H, d, J=2.1 Hz), 7.50-7.42 (1H, m), 7.42 (1H, s), 7.08 (1H,t, J=7.5 Hz), 6.96-6.89 (2H, m), 6.42-5.95 (2H, m), 4.35-4.23 (4H, m),3.92 (3H, s), 3.39 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz)

Example 285

Using the compound obtained in Example 272 and isobutyl bromide, whitepowdery1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, d, J=7.5 Hz), 7.57-7.44 (3H, m), 7.41 (1H,s), 7.08 (1H, t, J=7.5 Hz), 6.92-6.89 (2H, m), 6.23 (1H, tt, J=54.6, 3.9Hz), 4.29 (2H, td, J=12.9, 3.9 Hz), 3.90 (3H, s), 3.85 (2H, d, J=6.6Hz), 3.38 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 2.19 (1H, qt, J=6.6Hz), 1.05 (6H, d, J=6.6 Hz)

Example 286

Using the compound obtained in Reference Example 35 and the compoundobtained in Reference Example 70, pale yellow oily3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2methoxymethoxyphenyl)propan-1-onewas obtained following the procedure of Example 190.

¹H-NMR (CDCl₃) δ: 7.66 (1H, dd, J=7.8, 1.8 Hz), 7.56-7.38 (3H, m), 7.17(1H, d, J=8.4 Hz), 7.04 (1H, t, J=7.5 Hz), 6.92-6.88 (2H, m), 5.26 (2H,s), 4.21-4.08 (4H, m), 3.49 (3H, s), 3.40 (2H, t, J=7.2 Hz), 3.00 (2H,t, J=7.2 Hz), 1.51-1.45 (6H, m)

Example 287

Using the compound obtained in Example 286, white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-onewas obtained following the procedure of Example 266.

¹H-NMR (CDCl₃) δ: 12.25 (1H, s), 7.82 (1H, dd, J=8.1, 1.5 Hz), 7.60-7.43(4H, m), 6.98 (1H, d, J=8.4 Hz), 6.92-6.86 (2H, m), 4.21-4.10 (4H, m),3.44 (2H, t, J=7.2 Hz), 3.03 (2H, t, J=7.2 Hz), 1.51-1.43 (6H, m)

Example 288

Using the compound obtained in Example 287 and chlorodifluoromethane,white powdery 3-[2-(3,4-diethoxyphenyloxazol-4-yl)-1-(2-difluoromethoxyphenyl)propan-1-one was obtainedfollowing the procedure of Example 19.

¹H-NMR (CDCl₃) δ: 7.51 (1H, d, J=8.7 Hz), 7.60-7.45 (3H, m), 7.30 (1H,s), 7.28-7.19 (2H, m), 6.90 (1H, d, J=8.7 Hz), 6.58 (1H, t, J=75 Hz),4.15 (4H, q, J=7.2 Hz) 3.36 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),1.47 (6H, t, J=7.2 Hz)

Example 289

Using the compound obtained in Example 287 and the compound obtained inReference Example 84, white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.8 Hz), 7.56-7.41 (4H, m), 7.04(1H, td, J=7.5, 0.9 Hz), 6.95-6.88 (2H, m), 4.81 (2H, dt, J=47.1, 4.2Hz), 4.32 (2H, dt, J=27.3, 4.2 Hz), 4.21-4.10 (4H, m), 3.43 (2H, t,J=7.2 Hz) 3.00 (2H, t, J=7.2 Hz) 1.50-1.45 (6H, m)

Example 290

Using the compound obtained in Example 287 and the compound obtained inReference Example 85, white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.5, 1.8 Hz), 7.56-7.43 (3H, m), 7.41(1H, s), 7.08 (1H, t, J=7.5 Hz), 6.90 (1H, d, J=7.8 Hz), 6.23 (1H, tt,J=54.9, 3.9 Hz), 4.29 (2H, td, J=13.2, 3.9 Hz), 4.21-4.10 (4H, m), 3.38(2H, t, J=7.5 Hz) 2.98 (2H, t, J=7.5 Hz), 1.50-1.45 (6H, m)

Example 291

A 0.2 g quantity of the compound obtained in Example 223 and 0.1 ml oftriethylamine were dissolved in 5 ml of dichloromethane, 0.1 ml ofacetyl chloride was added to the obtained solution, and the mixture wasstirred for 6 hours at room temperature. At the completion of thereaction, water was added to the reaction mixture, and the obtainedmixture was extracted with ethyl acetate. The organic layer was washedtwice with water, and the solvent was distilled off. The residue waspurified using a silica gel column (n-hexane:ethyl acetate=2:1), and theobtained crude crystals were recrystallized with ethanol, therebyyielding 15 mg of white powdery2-{3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propionyl}phenylacetate.

¹H-NMR (CDCl₃) δ: 7.83 (1H, dd, J=7.8, 1.5 Hz), 7.60-7.50 (3H, m), 7.42(1H, s), 7.34-7.28 (1H, m), 7.12 (1H, dd, J=8.1, 0.9 Hz), 6.92 (1H, d,J=8.4 Hz), 4.69-4.61 (1H, m), 3.90 (3H, s), 3.32 (2H, t, J=7.2 Hz), 2.97(2H, t, J=7.2 Hz), 2.35 (3H, s), 1.40 (6H, d, J=6.0 Hz)

Example 292

Using the compound obtained in Reference Example 35 and1-(2-trifluoromethoxyphenyl)ethanone, white powdery3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-trifluoromethoxyphenyl)propan-1-onewas obtained following the procedure of Example 190.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.58-7.41 (3H, m), 7.38(1H, s), 7.35-7.29 (2H, m), 6.90 (1H, d, J=8.4 Hz), 4.20-4.10 (4H, m),3.34 (2H, t, J=6.9 Hz), 3.00 (2H, t, J=6.9 Hz), 1.48 (6H, t, J=6.9 Hz)

Example 293

Using the compound obtained in Reference Example 11 and1-(2-trifluoromethoxyphenyl)ethanone, white powdery3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-trifluoromethoxyphenyl)propan-1-one was obtained following the procedure ofExample 190.

¹H-NMR (CDCl₃) δ: 7.70 (1H, d, J=8.7 Hz), 7.57-7.53 (3H, m), 7.49 (1H,s), 7.42-7.30 (2H, m), 6.90 (1H, d, J=8.7 Hz), 3.94-3.91 (5H, m), 3.34(2H, t, J=7.2 Hz) 3.00 (2H, t, J=7.2 Hz), 1.42-1.30 (1H, m), 0.67-0.64(2H, m), 0.40-0.36 (2H, m)

Using the compound obtained in Reference Example 35 and thecorresponding acetophenone derivatives, compounds of Examples 294 to 299were obtained following the procedure of Example 190.

Example 2943-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,5-dimethoxyphenyl)propan-1-one

White Powder

¹H-NMR (CDCl₃) δ: 7.57-7.52 (2H, m), 7.40 (1H, s), 7.01 (1H, dd, J=9.0,3.3 Hz), 6.90 (2H, t, J=8.4 Hz), 4.20-4.10 (4H, m), 3.85 (3H, s), 3.78(3H, s), 3.39 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.47 (6H, t,J=6.9 Hz)

Example 2953-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-5-methylphenyl)propan-1-one

White Powder

¹H-NMR (CDCl₃) δ: 7.61-7.49 (3H, m), 7.40 (1H, s), 7.25-7.20 (2H, m),6.90 (1H, d, J=8.1 Hz), 6.83 (1H, d, J=8.4 Hz), 4.21-4.06 (6H, m), 3.41(2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 2.28 (3H, s), 1.53-1.40 (9H,m)

Example 2963-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,4-dimethylphenyl)propan-1-one

Colorless Powder

¹H-NMR (CDCl₃) δ: 7.63 (1H, d, J=8.4 Hz), 7.54 (1H, dd, J=8.4, 1.8 Hz),7.51 (1H, d, J=1.8 Hz), 7.42 (1H, s), 7.06-7.02 (2H, m), 6.90 (1H, d,J=8.4 Hz), 4.17 (2H, q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 3.30 (2H, t,J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.49 (3H, s), 2.34 (3H, s), 1.48 (6H,t, J=6.9 Hz)

Example 2973-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,5-dimethylphenyl)propan-1-one

Colorless Needle Crystals

¹H-NMR (CDCl₃) δ: 7.55 (1H, br s, J=8.7 Hz), 7.52 (1H, br s), 7.44 (1H,br d, J=8.7 Hz), 7.17-7.09 (2H, m), 6.90 (1H, d, J=8.7 Hz), 4.17 (2H, q,J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 3.29 (2H, t, J=7.2 Hz), 2.99 (2H, t,J=7.2 Hz), 2.44 (3H, s), 2.33 (3H, s), 1.47 (6H, t, J=6.9 Hz)

Example 2983-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-4-methylphenyl)propan-1-one

White Powder

¹H-NMR (CDCl₃) δ: 7.66 (1H, d, J=7.8 Hz), 7.60-7.51 (2H, m), 7.39 (1H,s), 6.90 (1H, d, J=8.4 Hz), 6.79 (1H, d, J=8.4 Hz), 6.73 (1H, s),4.21-4.08 (6H, m), 3.40 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 2.36(3H, s), 1.53-1.45 (9H, m)

Example 2993-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-4-fluorophenyl)propan-1-one

Colorless Needle Crystals

¹H-NMR (CDCl₃) δ: 7.78 (1H, dd, J=8.7, 7.2 Hz), 7.54 (1H, dd, J=8.4, 2.1Hz), 7.51 (1H, d, J=2.1 Hz), 7.39 (1H, br s), 6.90 (1H, d, J=8.4 Hz),6.71-6.61 (2H, m), 4.16 (2H, q, J=6.9 Hz), 4.14 (2H, q, J=6.9 Hz), 4.11(2H, q, J=6.9 Hz), 3.39 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.49(3H, t, J=6.9 Hz), 1.47 (6H, t, J=6.9 Hz)

Example 300

The compound obtained in Reference Example 54 and methyl(2-methoxymethyl)benzoate were used and treated following the procedureof Example 100, followed by treatment according to Reference Example 48,yielding white powdery 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-methoxymethylphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.74 (1H, dd, J=7.8, 1.2 Hz), 7.64-7.27 (6H, m), 6.91(1H, d, J=8.4 Hz), 4.73 (2H, s), 4.21-4.10 (4H, m), 3.43 (3H, s), 3.34(2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.51-1.43 (6H, m)

Using the compound obtained in Reference Example 54 and thecorresponding methyl benzoate derivatives, compounds of Examples 301 to303 were obtained following the procedure of the Example 300.

Example 3013-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethylphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.62-7.51 (4H, m), 7.43 (1H, s), 7.38-7.30 (2H, m),6.90 (1H, d, J=8.7 Hz), 4.18-4.13 (4H, m), 3.31 (2H, t, J=7.2 Hz), 3.00(2H, t, J=7.2 Hz), 2.81 (2H, q, J=7.5 Hz), 1.48 (6H, t, J=6.9 Hz), 1.20(3H, t, J=7.5 Hz)

Example 3023-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2,3-dimethoxyphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.56-7.51 (2H, m), 7.41 (1H, s), 7.18-7.01 (3H, m),6.90 (1H, d, J=8.4 Hz), 4.21-4.10 (4H, m), 3.89 (6H, s), 3.38 (2H, t,J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.48 (6H, t, J=6.9 Hz)

Example 3033-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(2-ethoxy-3-methylphenyl)propan-1-one

¹H-NMR (CDCl₃) δ: 7.55-7.51 (2H, m), 7.40 (1H, s), 7.36-7.29 (2H, m),7.04 (1H, t, J=7.2 Hz), 6.90 (1H, d, J=8.1 Hz), 4.20-4.11 (4H, m), 3.83(2H, q, J=7.5 Hz), 3.39 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 2.30(3H, s), 1.48 (6H, t, J=6.9 Hz), 1.26 (3H, t, J=6.9 Hz)

Example 304

Using the compound obtained in Reference Example 58 and1-(2-ethoxy-4-fluorophenyl)ethanone, pale yellow powdery1-(2-ethoxy-4-fluorophenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 190.

¹H-NMR (CDCl₃) δ: 7.77 (1H, t, J=7.8 Hz), 7.56 (1H, dd, J=8.4, 1.8 Hz),7.51 (1H, d, J=1.8 Hz), 7.40 (1H, s), 6.91 (1H, d, J=8.4 Hz), 6.71-6.61(2H, m), 4.21-4.07 (4H, m), 3.92 (3H, s), 3.39 (2H, t, J=7.2 Hz), 2.98(2H, t, J=7.2 Hz), 1.52-1.47 (6H, m)

Example 305

Using the compound obtained in Reference Example 58 and1-(4-fluoro-2-isopropoxyphenyl)ethanone, colorless oily3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(4-fluoro-2-isopropoxyphenyl)propan-1-one was obtained following the procedure of Example 190.

¹H-NMR (CDCl₃) δ: 7.77 (1H, t, J=7.8 Hz), 7.57 (1H, dd, J=8.4, 1.8 Hz),7.51 (1H, d, J=1.8 Hz), 7.40 (1H, s), 6.91 (1H, d, J=8.4 Hz), 6.71-6.61(2H, m), 4.63 (1H, sept, J=6.0 Hz), 4.18 (2H, q, J=6.9 Hz), 3.92 (3H,s), 3.38 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 1.50 (3H, t, J=6.9Hz), 1.42 (6H, d, J=6.0 Hz)

Example 306

Using the compound obtained in Reference Example 68 and1-(2-ethoxy-5-methylphenyl)ethanone, white powdery1-(2-ethoxy-5-methylphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 190.

¹H-NMR (CDCl₃) δ: 7.60-7.40 (3H, m), 7.39 (1H, s), 7.24-7.19 (1H, m),6.91 (1H, d, J=8.1 Hz), 6.83 (1H, d, J=8.4 Hz), 4.69-4.58 (1H, m), 4.10(2H, q, J=6.9 Hz), 3.89 (3H, s), 3.41 (2H, t, J=7.2 Hz), 2.98 (2H, t,J=7.2 Hz), 2.29 (3H, s), 1.48-1.38 (9H, m)

Example 307

Using the compound obtained in Reference Example 68 and1-(2-ethoxy-4-methylphenyl)ethanone, white powdery1-(2-ethoxy-4-methylphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-onewas obtained following the procedure of Example 190.

¹H-NMR (CDCl₃) δ: 7.66 (1H, d, J=8.1 Hz), 7.59-7.53 (2H, m), 7.39 (1H,s), 6.91 (1H, d, J=8.4 Hz), 6.79 (1H, d, J=8.1 Hz), 6.73 (1H, s),4.58-4.71 (1H, m), 4.12 (2H, q, J=6.9 Hz), 3.90 (1H, s) 3.40 (2H, t,J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz), 2.36 (3H, s), 1.48 (3H, t, J=6.9 Hz),1.40 (6H, d, J=6.0 Hz)

Example 308

Using the compound obtained in Example 136 and chlorodifluoromethane,white powdery3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 4.

¹H-NMR (CDCl₃) δ: 8.50 (1H, m), 7.83 (1H, dd, J=8.4, 2.1 Hz), 7.78 (1H,d, J=2.1 Hz), 7.58 (1H, d, J=7.8 Hz), 7.47 (1H, s), 7.32 (1H, m), 7.00(1H, d, J=8.4 Hz), 6.58 (1H, t, J=74.7 Hz), 3.93 (3H, s), 3.59 (2H, t,J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.57 (3H, s)

Example 309

Using the compound obtained in Example 136 and the compound obtained inReference Example 85, white powdery3-{2-[3-(2,2-difluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure ofExample 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 0.9 Hz), 7.66 (1H, dd, J=8.4, 2.1Hz), 7.60-7.54 (2H, m), 7.46 (1H, s), 7.35-7.31 (1H, m), 6.94 (1H, d,J=8.7 Hz), 6.16 (1H, tt, J=54.9, 1.2 Hz) 4.29 (2H, td, J=12.9, 1.2 Hz),3.92 (3H, s), 3.61 (2H, t, J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz), 2.58 (3H,s)

Example 310

Using the compound obtained in Example 136 and the compound obtained inReference Example 84, white powdery3-{2-[3-(2-fluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50-8.49 (1H, m), 7.63-7.54 (3H, m), 7.45 (1H, s),7.34-7.27 (1H, m), 6.93 (1H, d, J=8.7 Hz), 4.88 (1H, t, J=4.2 Hz), 4.72(1H, t, J=4.2 Hz) 4.39 (1H, t, J=4.2 Hz), 4.30 (1H, t, J=4.2 Hz), 3.92(3H, s), 3.60 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.57 (3H, s)

Example 311

Using the compound obtained in Example 136 and 2-bromobutane, yellowoily3-[2-(3-sec-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.59-7.55 (3H, m), 7.54(1H, s), 7.45-7.30 (1H, m), 6.91 (1H, d, J=8.4 Hz), 4.43-4.37 (1H, m),3.89 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H,s), 1.86-1.62 (2H, m), 1.34 (3H, d, J=6.6 Hz), 1.00 (3H, t, J=6.6 Hz)

Example 312

Using the compound obtained in Example 136 and 3-bromopentane, whitepowdery 3-{2-[3-(1-ethylpropoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtainedfollowing the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.61-7.53 (3H, m), 7.45(1H, s), 7.34-7.30 (1H, m), 6.91 (1H, d, J=8.1 Hz), 4.28-4.20 (1H, m),3.89 (3H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H,s), 1.78-1.68 (4H, m), 0.98 (6H, t, J=6.6 Hz)

Example 313

Using the compound obtained in Example 101 and chlorodifluoromethane,white powdery3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-onewas obtained following the procedure of Example 4.

¹H-NMR (CDCl₃) δ: 7.85-7.80 (2H, m), 7.70 (1H, m), 7.50-7.40 (2H, m),7.0-6.9 (3H, m), 6.58 (1H, t, J=74.4 Hz), 4.14 (2H, q, J=6.9 Hz), 3.93(3H, s), 3.42 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.48 (3H, t,J=6.9 Hz)

Example 314

Using the compound obtained in Example 101 and the compound obtained inReference Example 85, white powdery3-{2-[3-(2,2-difluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.73-7.63 (2H, m), 7.55 (1H, d, J=2.1 Hz), 7.46-7.39(2H, m), 7.01-6.91 (3H, m), 6.16 (1H, tt, J=54.9, 1.2 Hz), 4.29 (2H, td,J=12.9, 1.2 Hz), 4.14 (2H, q, J=6.9 Hz), 3.91 (3H, s), 3.43 (2H, t,J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz)

Example 315

Using the compound obtained in Example 101 and the compound obtained inReference Example 84, white powdery1-(2-ethoxyphenyl)-3-{2-[3-(2-fluoroethoxy)-4-methoxyphenyl]oxazol-4-yl}propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.69 (1H, dd, J=7.8, 1.8 Hz), 7.61 (1H, dd, J=8.4, 1.8Hz), 7.55 (1H, s), 7.44-7.39 (2H, m), 7.00-6.91 (3H, m), 4.81 (2H, dt,J=47.4, 4.2 Hz), 4.32 (2H, dt, J=23.1, 4.2 Hz), 4.17-4.10 (2H, m), 3.90(3H, s), 3.41 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 1.46 (3H, t,J=5.7 Hz)

Reference Example 86

Using the compound obtained in Reference Example 59 and the compoundobtained in Reference Example 85, white powdery ethyl4-benzyloxy-3-(2,2-difluoroethoxy)benzoate was obtained following theprocedure of Example 4.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=8.4, 2.1 Hz), 7.61 (1H, d, J=2.1 Hz),7.44-7.29 (5H, m), 6.95 (1H, d, J=8.4 Hz), 6.11 (1H, tt, J=54.9, 4.2Hz), 5.19 (2H, s), 4.38-4.21 (4H, m), 1.39 (3H, t, J=7.2 Hz)

Reference Example 87

Using the compound obtained in Reference Example 86, white powdery4-benzyloxy-3-(2,2-difluoroethoxy)benzoic acid was obtained followingthe procedure of Reference Example 3.

¹H-NMR (DMSO d₆) δ: 7.61 (1H, dd, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8Hz), 7.50-7.30 (5H, m), 7.18 (1H, d, J=8.4 Hz), 6.38 (1H, tt, J=54.3,3.6 Hz), 5.22 (2H, s), 4.37 (2H, td, J=14.7, 3.6 Hz)

Reference Example 88

Using the compound obtained in Reference Example 87, white powdery4-benzyloxy-3-(2,2-difluoroethoxy)benzamide was obtained following theprocedure of Reference Example 4.

¹H-NMR (DMSO d₆) δ: 7.86 (1H, br s), 7.56-7.29 (7H, m), 7.25 (1H, br s),7.14 (1H, d, J=8.4 Hz), 6.40 (1H, tt, J=54.3, 3.6 Hz), 5.20 (2H, s),4.34 (2H, td, J=14.7, 3.6 Hz)

Reference Example 89

Using the compound obtained in Reference Example 88, white powdery2-[4-benzyloxy-3-(2,2-difluoroethoxy)phenyl]-4-chloromethyloxazole wasobtained following the procedure of Reference Example 5.

¹H-NMR (CDCl₃) δ: 7.68-7.60 (3H, m), 7.45-7.30 (5H, m), 7.01 (1H, d,J=8.4 Hz), 6.12 (1H, tt, J=54.9, 4.2 Hz) 5.18 (2H, s), 4.56 (2H, s),4.30 (2H, td, J=13.2, 4.2 Hz)

Reference Example 90

Using the compound obtained in Reference Example 89, white powderydimethyl2-{2-[4-benzyloxy-3-(2,2-difluoroethoxy)phenyl]oxazol-4-ylmethyl}malonatewas obtained following the procedure of Reference Example 47.

¹H-NMR (CDCl₃) δ: 7.63-7.57 (2H, m), 7.45-7.30 (6H, m), 6.99 (1H, d,J=8.1 Hz), 6.12 (1H, tt, J=54.9, 4.2 Hz), 5.18 (2H, s), 4.29 (2H, td,J=13.2, 4.2 Hz), 3.89 (2H, t, J=7.5 Hz), 3.75 (6H, s), 3.18 (2H, t,J=7.5 Hz)

Reference Example 91

Using the compound obtained in Reference Example 90, brownish oilymethyl 3-{2-[4-benzyloxy-3-(2,2-difluoroethoxy)phenyl]oxazol-4-yl}-propionate was obtained following theprocedure of Reference Example 48.

¹H-NMR (CDCl₃) δ: 7.64-7.59 (2H, m), 7.42-7.33 (6H, m), 6.99 (1H, d,J=8.1 Hz), 6.12 (1H, tt, J=54.9, 4.2 Hz), 5.18 (2H, s), 4.29 (2H, td,J=13.2, 4.2 Hz), 3.68 (3H, s), 2.91 (2H, t, J=7.5 Hz), 2.72 (2H, t,J=7.5 Hz)

Example 316

Using the compound obtained in Reference Example 91, pale yellow oilymethyl2-{2-[4-benzyloxy-3-(2,2-difluoroethoxy)-phenyl]oxazol-4-ylmethyl}-3-(3-methylpyridin-2-yl)-3-oxopropionatewas obtained following the procedure of Example 100.

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.60-7.52 (3H, m), 7.46-7.30(7H, m), 6.97 (1H, d, J=8.1 Hz), 6.11 (1H, tt, J=54.9, 4.2 Hz),5.24-5.16 (3H, m), 4.27 (2H, td, J=13.2, 4.2 Hz), 3.66 (3H, s),3.34-3.22 (2H, m), 2.60 (3H, s)

Example 317

Using the compound obtained in Example 316, white powdery3-{2-[3-(2,2-difluoroethoxy)-4-hydroxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 136.

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.61-7.57 (2H, m), 7.52 (1H,s), 7.45 (1H, s), 7.34-7.30 (1H, m), 7.00 (1H, d, J=8.1 Hz), 6.11 (1H,tt, J=54.9, 4.2 Hz), 6.07 (1H, s), 4.32 (2H, td, J=13.2, 4.2 Hz), 3.59(2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 2.57 (3H, s)

Example 318

Using the compound obtained in Example 317 and methyl iodide, whitepowdery3-{2-[3-(2,2-difluoroethoxy)-4-ethoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)-propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.51 (1H, d, J=4.5 Hz), 7.66-7.57 (3H, m), 7.46 (1H,s), 7.34-7.30 (1H, m), 6.94 (1H, d, J=8.4 Hz), 6.14 (1H, tt, J=54.6, 3.9Hz), 4.28 (2H, td, J=12.9, 3.9 Hz), 4.13 (2H, q, J=6.9 Hz), 3.60 (2H, t,J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.47 (3H, t, J=6.9 Hz)

Example 319

Using the compound obtained in Example 317 and 2-bromopropane, whitepowdery3-{2-[3-(2,2-difluoroethoxy)-4-isopropoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.51 (1H, d, J=4.5 Hz), 7.65-7.57 (3H, m), 7.46 (1H,s), 7.34-7.30 (1H, m), 6.95 (1H, d, J=8.4 Hz), 6.12 (1H, tt, J=54.6, 3.9Hz), 4.62-4.54 (1H, m), 4.26 (2H, td, J=12.9, 3.9 Hz), 3.60 (2H, t,J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s), 1.37 (6H, d, J=6.0 Hz)

Example 320

Using the compound obtained in Reference Example 7 and 2-difluoromethoxybenzoic acid, white powderyN-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-difluoromethoxybenzamidewas obtained following the procedure of Example 1.

¹H-NMR (CDCl₃) δ: 8.10 (1H, dd, J=7.8, 1.8 Hz), 7.64-7.57 (3H, m),7.51-7.45 (4H, m), 7.40-7.26 (4H, m), 7.15 (1H, d, J=8.4 Hz), 6.95 (1H,d, J=9.0 Hz), 6.59 (1H, t, J=72.9 Hz), 5.20 (2H, s), 4.61 (2H, d, J=5.4Hz), 3.93 (3H, s)

Example 321

Using the compound obtained in Example 320, white powdery2-difluoromethoxy-N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-benzamidewas obtained following the procedure of Example 2.

¹H-NMR (CDCl₃) δ: 8.09 (1H, d, J=7.8 Hz), 7.64-7.45 (5H, m), 7.32 (1H,t, J=7.8 Hz), 7.15 (1H, d, J=7.8 Hz), 6.91 (1H, d, J=8.4 Hz), 6.60 (1H,t, J=72.9 Hz), 5.77 (1H, s), 4.61 (2H, d, J=5.1 Hz), 3.94 (3H, s)

Example 322

Using the compound obtained in Example 321 and allyl bromide, whitepowderyN-[2-(3-allyloxy-4-methoxyphenyl)-oxazol-4-ylmethyl]-2-difluoromethoxybenzamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.10 (1H, d, J=7.8 Hz), 7.64-7.30 (6H, m), 7.15 (1H,d, J=8.4 Hz), 6.94 (1H, d, J=8.1 Hz), 6.61 (1H, t, J=75 Hz), 6.17-6.08(1H, m), 5.45 (1H, dd, J=17.1, 1.5 Hz), 5.32 (1H, dd, J=10.5, 1.5 Hz),4.70 (2H, t, J=5.4 Hz), 4.62 (2H, t, J=5.4 Hz), 3.93 (3H, s)

Example 323

Using the compound obtained in Example 321 and 2-bromopropane, whitepowdery2-difluoromethoxy-N-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-ylmethyl]benzamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.10 (1H, d, J=7.8 Hz), 7.64-7.30 (6H, m), 7.15 (1H,d, J=8.4 Hz), 6.94 (1H, d, J=8.1 Hz), 6.61 (1H, t, J=75 Hz), 4.70-4.61(5H, m), 3.91 (3H, s), 1.39 (6H, d, J=6.0 Hz)

Example 324

Using the compound obtained in Example 17 and 3-bromopentane, whitepowdery N-{2-[3-(1-ethylpropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-3-methylpicolinamide was obtained followingthe procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, d, J=4.5 Hz), 7.63-7.55(4H, m), 7.32-7.28 (1H, m), 6.92 (1H, d, J=8.4 Hz), 4.59 (2H, d, J=6.0Hz), 4.28-4.20 (1H, m), 3.90 (3H, s), 2.76 (3H, s), 1.82-1.68 (4H, m),0.99 (6H, t, J=7.5 Hz)

Example 325

Using the compound obtained in Example 2 and 3-bromopentane, whitepowdery2-ethoxy-N-{2-[3-(1-ethylpropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}benzamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.24 (1H, dd, J=8.1, 1.8 Hz),7.62-7.56 (3H, m), 7.45-7.39 (1H, m), 7.07 (1H, t, J=8.1 Hz), 6.96-6.91(2H, m), 4.63 (2H, dd, J=5.4, 0.9 Hz), 4.26-4.14 (3H, m), 3.90 (3H, s),1.79-1.69 (4H, m), 1.49 (3H, t, J=7.2 Hz), 1.00 (6H, t, J=7.2 Hz)

Reference Example 92

Using the compound obtained in Reference Example 44, colorless oilydimethyl 2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]malonate was obtained following the procedureof Reference Example 47.

¹H-NMR (CDCl₃) δ: 7.70 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.48-7.22 (6H,m), 6.62 (1H, t, J=74.7 Hz), 5.21 (2H, s), 3.90 (1H, t, J=7.5 Hz), 3.73(6H, s), 3.20 (2H, t, J=7.5 Hz)

Reference Example 93

Using the compound obtained in Reference Example 92, pale yellow oilymethyl 3-[2-(3-benzyloxy-4-difluoromethoxy phenyl)oxazol-4-yl]propionatewas obtained following the procedure of Reference Example 48.

¹H-NMR (CDCl₃) δ: 7.71 (1H, d, J=1.8 Hz), 7.48-7.31 (6H, m), 7.24 (1H,d, J=8.4 Hz), 6.62 (1H, t, J=74.7 Hz), 5.21 (2H, s), 3.70 (3H, s), 2.93(2H, t, J=7.2 Hz), 2.71 (2H, t, J=7.2 Hz)

Example 326

Using the compound obtained in Reference Example 93, colorless oilymethyl 2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxo propionate wasobtained following the procedure of Example 100.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.8, 1.2 Hz), 7.67-7.30 (10H, m), 7.21(1H, d, J=8.4 Hz), 6.60 (1H, t, J=74.7 Hz), 5.18 (2H, s), 4.11 (1H, t,J=7.2 Hz), 3.65 (3H, s), 3.45-3.20 (2H, m), 2.60 (3H, s)

Example 327

The compound obtained in Example 326 was used and treated following theprocedure of Example 125, followed by treatment according to theprocedure of Example 2, yielding white powdery3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.67-7.45 (4H, m),7.33-7.30 (1H, m), 7.16 (1H, d, J=8.1 Hz), 6.58 (1H, t, J=75 Hz), 5.76(1H, s), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.57 (3H, s)

Example 328

A 0.15 quantity of the compound obtained in Example 327 and 0.18 ml of1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3 ml of ethanol,0.15 g of (bromomethyl)cyclopropane was then added to the obtainedsolution, and the obtained mixture was heated and refluxed overnight.After cooling, water was added to the obtained reaction mixture, andethyl acetate extraction was performed. The organic layer was washedtwice with water and concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallizedfrom aqueous 80% ethanol, thereby yielding 42 mg of white powdery3-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.51 (1H, dd, J=4.8, 1.2 Hz), 7.60-7.53 (3H, m), 7.50(1H, s), 7.35-7.31 (1H, m), 7.21 (1H, d, J=8.1 Hz), 6.68 (1H, t, J=75.3Hz), 3.95 (2H, d, J=6.9 Hz), 3.60 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5Hz), 2.58 (3H, s), 1.37-1.25 (1H, m), 0.69-0.63 (2H, m), 0.40-0.34 (2H,m)

Example 329

A 80 mg quantity of the compound obtained in Example 327 and 0.09 ml of1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 2 ml of ethanol, 80mg of 1-bromopropane was then added to the obtained solution, and heatedand refluxed overnight. After cooling, water was added to the obtainedreaction mixture, and ethyl acetate extraction was performed. Theorganic layer was washed twice with water, concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1). The obtained crystals wererecrystallized from aqueous 80% ethanol, thereby yielding 25 mg of whitepowdery3-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.51 (1H, dd, J=4.8, 1.2 Hz), 7.61-7.53 (3H, m), 7.50(1H, s), 7.35-7.31 (1H, m), 7.20 (1H, d, J=8.1 Hz), 6.61 (1H, t, J=75Hz), 4.07 (2H, t, J=6.6 Hz), 3.60 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5Hz), 2.58 (3H, s), 1.87 (2H, td, J=7.5, 6.6 Hz), 1.07 (3H, t, J=7.5 Hz)

Example 330

A 0.15 g quantity of the compound obtained in Example 327 and 0.18 ml of1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3 ml of ethanol,0.15 g of allyl bromide was then added to the obtained solution, andheating and refluxing were conducted for 2 hours. After cooling, waterwas added to the obtained reaction mixture, and ethyl acetate wasperformed. The organic layer was washed twice with water, concentrated,and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1). The obtained crystals wererecrystallized from aqueous 80% ethanol, thereby yielding 70 mg of whitepowdery3-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.

¹H-NMR (CDCl₃) δ: 8.51 (1H, dd, J=4.5, 1.2 Hz), 7.62-7.56 (3H, m), 7.50(1H, s), 7.50-7.31 (1H, m), 7.22 (1H, d, J=8.4 Hz), 6.62 (1H, t, J=75Hz), 6.12-6.02 (1H, m), 5.46 (1H, dd, J=17.4, 1.5 Hz), 5.33 (1H, dd,J=10.8, 1.5 Hz), 4.68 (2H, d, J=8.1 Hz), 3.61 (2H, t, J=7.2 Hz), 3.02(2H, t, J=7.2 Hz), 2.58 (3H, s)

Example 331

An 80 mg quantity of the compound obtained in Example 327 and 0.09 ml of1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 2 ml of ethanol,and 80 mg of 4-bromo-1-butene was then added to the obtained solution,and heating and refluxing were conducted overnight. After cooling, waterwas added to the obtained reaction mixture, and ethyl acetate extractionwas performed. The organic layer was washed twice with water,concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=3:1). The obtained crystals were recrystallized from aqueous 80%ethanol, thereby yielding 22 mg of white powdery3-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)-oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.51 (1H, dd, J=4.8, 1.2 Hz), 7.61-7.54 (3H, m), 7.50(1H, s), 7.35-7.31 (1H, m), 7.20 (1H, d, J=8.4 Hz), 6.62 (1H, t, J=75Hz), 5.98-5.83 (1H, m), 5.24-5.12 (2H, m), 4.16 (2H, t, J=6.6 Hz), 3.61(2H, t, J=7.2 Hz), 3.03 (2H, t, J=7.2 Hz), 2.64-2.58 (5H, m)

Example 332

A 0.15 g quantity of the compound obtained in Example 327 and 0.18 ml ofDBU were dissolved in 3 ml of ethanol, 0.15 g of 2-bromopropane was thenadded to the obtained solution, and heating and refluxing were conductedovernight. After cooling, water was added to the reaction mixture, andethyl acetate extraction was performed. The organic layer was washedtwice with water, concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1). The obtained crystals were recrystallized from aqueous 80%ethanol, thereby yielding 70 mg of white powdery3-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one

¹H-NMR (CDCl₃) δ: 8.51 (1H, dd, J=4.8, 0.9 Hz), 7.63-7.53 (3H, m), 7.50(1H, s), 7.35-7.31 (1H, m), 7.20 (1H, d, J=8.1 Hz), 6.61 (1H, t, J=75Hz), 4.73-4.65 (1H, m), 3.61 (2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz),2.58 (3H, s), 1.39 (6H, d, J=6.0 Hz)

Example 333

Using the compound obtained in Example 327 and ethyl iodide, whitepowdery3-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 330.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.5, 1.2 Hz), 7.61-7.49 (4H, m),7.35-7.30 (1H, m), 7.20 (1H, d, J=8.4 Hz), 6.62 (1H, t, J=75 Hz), 4.18(2H, q, J=6.9 Hz), 3.61 (2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.2 Hz), 2.58(3H, s), 1.47 (3H, t, J=6.9 Hz)

Example 334

A 60 mg quantity of the compound obtained in Example 229 and 0.2 ml ofDBU were dissolved in 4 ml of ethanol, 0.2 ml of ethyl iodide was thenadded to the obtained solution, and heating and refluxing were conductedfor 2 hours. After cooling, water was added to the reaction mixture, andethyl acetate extraction was performed. The organic layer was washedtwice with water, concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1). The obtained crystals were recrystallized from ethanol,thereby yielding 36 mg of white powdery3-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.5, 1.8 Hz), 7.60-7.34 (4H, m),7.01-6.91 (2H, m), 7.20 (1H, d, J=8.1 Hz), 6.62 (1H, t, J=75 Hz),4.22-4.07 (4H, m), 3.43 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),1.50-1.40 (6H, m)

Example 335

A 0.15 g quantity of the compound obtained in Example 229 and 0.17 ml ofDBU were dissolved in 4 ml of ethanol, 0.14 g of ally bromide was thenadded to the obtained solution, and heating and refluxing were conductedfor 2 hours. After cooling, water was added to the obtained reactionmixture, and ethyl acetate extraction was performed. The organic layerwas washed twice with water, concentrated under reduced pressure, andthe obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallizedfrom aqueous 80% ethanol, thereby yielding 90 mg of white powdery3-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.5, 1.8 Hz), 7.62-7.56 (2H, m),7.46-7.40 (2H, m), 7.22 (1H, d, J=8.1 Hz), 7.01-6.92 (2H, m), 6.62 (1H,t, J=75 Hz), 6.15-6.00 (1H, m), 5.45 (1H, dd, J=17.1, 1.5 Hz), 5.32 (1H,dd, J=10.5, 1.5 Hz), 4.67 (2H, d, J=8.1 Hz), 4.14 (2H, q, J=6.9 Hz),3.42 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 1.48 (3H, t, J=6.9 Hz)

Example 336

A 0.12 g quantity of the compound obtained in Example 229 and 0.14 ml ofDBU were dissolved in 3 ml of ethanol, 0.12 g of(bromomethyl)cyclopropane was then added to the obtained solution, andheating and refluxing were conducted overnight. After cooling, water wasadded to the obtained reaction mixture, and ethyl acetate extraction wasperformed. The organic layer was washed twice with water, concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=3:1). The obtainedcrystals were recrystallized from ethanol, thereby yielding 80 mg ofwhite powdery 3-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.71 (1H, dd, J=7.8, 1.8 Hz), 7.59-7.54 (2H, m),7.46-7.40 (2H, m), 7.21 (1H, d, J=8.1 Hz), 7.01-6.95 (2H, m), 6.68 (1H,t, J=75 Hz), 4.14 (2H, q, J=6.9 Hz), 3.95 (2H, d, J=6.9 Hz), 3.42 (2H,t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 1.47 (3H, t, J=6.9 Hz), 1.34-1.28(1H, m), 0.69-0.63 (2H, m), 0.40-0.34 (2H, m)

Example 337

A 0.12 g quantity of the compound obtained in Example 229 and 0.14 ml ofDBU were dissolved in 3 ml of ethanol, 0.12 g of 4-bromo-1-butene wasthen added to the obtained solution, and heating and refluxing wereconducted overnight. After cooling, water was added to the obtainedreaction mixture, and ethyl acetate extract was performed. The organiclayer was washed twice with water, concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1). The obtained crystals wererecrystallized from ethanol, thereby yielding 80 mg of white powdery3-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.70 (1H, dd, J=7.8, 1.8 Hz), 7.61-7.54 (2H, m),7.45-7.40 (2H, m), 7.20 (1H, d, J=8.1 Hz), 7.00-6.92 (2H, m), 6.62 (1H,t, J=75 Hz), 5.97-5.83 (1H, m), 5.23-5.12 (2H, m), 4.18-4.10 (4H, m),3.42 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.63-2.56 (4H, m), 1.47(3H, t, J=6.9 Hz)

Example 338

Using the compound obtained in Example 97 and ethyl iodide, whitepowderyN-[2-(4-difluoromethoxy-3-ethoxyphenyl)-oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.39 (1H, d, J=3.6 Hz), 7.67-7.57(4H, m), 7.33-7.20 (2H, m), 6.63 (1H, t, J=75 Hz), 4.60 (2H, d, J=5.7Hz), 4.20 (2H, q, J=6.9 Hz), 2.76 (3H, s), 1.48 (3H, t, J=6.9 Hz)

Example 339

Using the compound obtained in Example 97 and allyl bromide, white solidN-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained followingthe procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.40-8.39 (1H, m), 7.67 (1H, s),7.65-7.58 (3H, m), 7.33-7.22 (3H, m), 6.63 (1H, t, J=75 Hz), 6.13-6.03(1H, m), 5.50-5.32 (2H, m), 4.70-4.68 (2H, m), 4.60 (2H, d, J=8.7 Hz),2.76 (3H, s)

Example 340

Using the compound obtained in Example 97 and 1-bromopropane, whitepowderyN-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, d, J=7.8, Hz), 7.67-7.57(4H, m), 7.33-7.20 (2H, m), 6.62 (1H, t, J=75 Hz), 4.60 (2H, d, J=6.0Hz), 4.08 (2H, t, J=6.6 Hz), 2.76 (3H, s), 1.94-1.82 (2H, m), 1.07 (3H,t, J=7.5 Hz)

Example 341

Using the compound obtained in Example 97 and 2-bromopropane, whitesolidN-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39-8.38 (1H, m), 7.67-7.57 (4H, m),7.33-7.19 (2H, m), 6.62 (1H, t, J=75 Hz), 4.74-4.67 (1H, m), 4.59 (2H,d, J=6.0 Hz), 2.76 (3H, s), 1.39 (6H, d, J=6.0 Hz)

Example 342

Using the compound obtained in Example 97 and 3-bromopentane, colorlessoilyN-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethyl}-3-methylpicolinamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.40-8.38 (1H, m), 7.67 (1H, s),7.63-7.55 (3H, m), 7.33-7.20 (3H, m), 6.61 (1H, t, J=75 Hz), 4.59 (2H,d, J=6.0 Hz), 4.33 (1H, qt, J=6.0 Hz), 2.76 (3H, s), 1.79-1.70 (4H, m),0.98 (6H, t, J=7.2 Hz)

Example 343

Using the compound obtained in Example 97 and 4-bromo-1-butene,colorless oily N-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained followingthe procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.40-8.38 (1H, m), 7.67 (1H, s),7.64-7.58 (3H, m), 7.33-7.20 (2H, m), 6.63 (1H, t, J=75 Hz), 5.95-5.84(1H, m), 5.23-5.13 (2H, m), 4.61-4.59 (2H, m), 4.18 (2H, t, J=6.6 Hz),2.76 (3H, s), 2.64-2.58 (2H, m)

Example 344

Using the compound obtained in Example 97 and isobutyl bromide,colorless oily N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained followingthe procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.39 (1H, br s), 7.68 (1H, s),7.62-7.57 (3H, m), 7.33-7.20 (2H, m), 6.61 (1H, t, J=75 Hz), 4.60 (2H,d, J=6.0 Hz), 3.88 (2H, d, J=6.3 Hz), 2.76 (3H, s), 2.19-2.04 (1H, m),1.06 (6H, d, J=6.3 Hz)

Example 345

Using the compound obtained in Example 97 and (bromomethyl)cyclobutane,colorless oily N-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methyl picolinamidewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.40 (1H, br s), 7.68 (1H, s),7.64-7.59 (3H, m), 7.33-7.20 (2H, m), 6.61 (1H, t, J=75 Hz), 4.60 (2H,d, J=6.0 Hz), 4.08 (2H, d, J=6.6 Hz), 2.89-2.76 (4H, m), 2.25-2.12 (2H,m), 2.04-1.92 (4H, m)

Example 346

Using the compound obtained in Reference Example 46 and 2-ethoxybenzoicacid, white powdery N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtainedfollowing the procedure of Example 96.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz), 7.73(1H, d, J=1.8 Hz), 7.68-7.61 (2H, m), 7.48-7.24 (7H, m), 7.07 (1H, t,J=8.1 Hz), 6.95 (1H, d, J=8.4 Hz), 6.63 (1H, t, J=75 Hz), 5.21 (2H, s),4.63 (2H, d, J=5.4 Hz), 4.18 (2H, q, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)

Example 347

Using the compound obtained in Example 346, white powderyN-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamidewas obtained following the procedure of Example 97.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz),7.71-7.60 (2H, m), 7.57 (1H, dd, J=8.4, 1.8 Hz), 7.46-7.39 (1H, m), 7.19(1H, d, J=8.4 Hz), 7.07 (1H, t, J=8.1 Hz), 6.95 (1H, d, J=8.4 Hz), 6.61(1H, t, J=73.2 Hz), 6.02 (1H, br s), 4.64 (2H, dd, J=5.4, 0.9 Hz), 4.19(2H, q, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz)

Example 348

A 80 mg quantity of the compound obtained in Example 347 and 0.1 ml ofDBU were dissolved in 2 ml of ethanol, 80 mg of isobutyl bromide wasthen added to the obtained solution, and heating and refluxing wereconducted overnight. After cooling, water was added to the obtainedreaction mixture, and ethyl acetate extraction was performed. Theorganic layer was washed twice with water, concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1). The obtained crystals wererecrystallized from aqueous 80% ethanol, thereby yielding 30 mg of whitepowderyN-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.

¹H-NMR (CDCl₃) δ: 8.54 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz), 7.67(1H, s), 7.66-7.57 (2H, m), 7.45-7.39 (1H, m), 7.23 (1H, d, J=8.1 Hz),7.07 (1H, t, J=8.1 Hz), 6.95 (1H, d, J=7.5 Hz), 6.62 (1H, t, J=75 Hz),4.64 (2H, d, J=5.1 Hz), 4.19 (2H, q, J=6.9 Hz), 3.87 (2H, d, J=6.6 Hz),2.17 (1H, qt, J=6.6 Hz), 1.49 (3H, t, J=6.9 Hz), 1.07 (6H, d, J=6.9 Hz)

Example 349

Using the compound obtained in Example 347 and ethyl iodide, whitepowderyN-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamidewas obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz),7.67-7.58 (3H, m), 7.46-7.40 (1H, m), 7.24-7.21 (1H, m), 7.08 (1H, t,J=7.8 Hz), 6.95 (1H, d, J=7.8 Hz), 6.64 (1H, t, J=75 Hz) 4.63 (1H, d,J=5.1 Hz), 4.23-4.15 (4H, m), 1.52-1.46 (6H, m)

Example 350

Using the compound obtained in Example 347 and 1-bromopropane, whitepowdery N-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following theprocedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.24 (1H, dd, J=7.5, 1.8 Hz), 7.67(1H, s), 7.64-7.57 (2H, m), 7.46-7.40 (1H, m), 7.23 (1H, d, J=7.8 Hz),7.07 (1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz), 6.63 (1H, t, J=75 Hz),4.64 (2H, d, J=5.4 Hz), 4.19 (2H, q, J=7.2 Hz), 4.07 (2H, t, J=6.6 Hz),1.90 (2H, qt, J=7.2, 6.6 Hz), 1.49 (3H, t, J=6.9 Hz), 1.08 (3H, t, J=7.2Hz)

Example 351

Using the compound obtained in Example 347 and allyl bromide, whitepowdery N-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following theprocedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.55 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz), 7.68(1H, s), 7.65-7.60 (2H, m), 7.46-7.40 (1H, m), 7.25-7.23 (1H, m), 7.08(1H, t, J=7.8 Hz), 6.96 (1H, d, J=8.4 Hz), 6.64 (1H, t, J=74.7 Hz),6.10-6.03 (1H, m), 5.47 (1H, dd, J=17.4, 1.5 Hz), 5.34 (1H, dd, J=10.5,1.5 Hz), 4.69 (2H, dt, J=5.1, 1.5 Hz), 4.63 (2H, dd, J=5.4, 1.2 Hz),4.19 (2H, q, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz)

Example 352

Using the compound obtained in Example 347 and 2-bromopropane, whitepowderyN-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamidewas obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.24 (1H, dd, J=7.5, 1.8 Hz), 7.67(1H, s), 7.65-7.57 (2H, m), 7.46-7.40 (1H, m), 7.26-7.21 (1H, m), 7.08(1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz), 6.63 (1H, t, J=75 Hz),4.74-4.62 (3H, m), 4.19 (2H, q, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz), 1.40(6H, d, J=6.3 Hz)

Example 353

Using the compound obtained in Example 347 and(bromomethyl)cyclopropane, white powdery N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy benzamidewas obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.55 (1H, br s), 8.24 (1H, dd, J=8.1, 1.8 Hz), 7.67(1H, s), 7.61-7.58 (2H, m), 7.46-7.39 (1H, m), 7.26-7.21 (1H, m), 7.07(1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz), 6.70 (1H, t, J=75 Hz) 4.63(2H, dd, J=5.4, 0.9 Hz), 4.19 (2H, q, J=6.9 Hz), 1.49 (3H, t, J=6.9 Hz),1.35-1.30 (1H, m), 0.71-0.64 (2H, m), 0.41-0.35 (2H, m)

Example 354

Using the compound obtained in Example 347 and 4-bromo-1-butene, whitepowdery N-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following theprocedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.24 (1H, dd, J=7.5, 1.8 Hz), 7.67(1H, s), 7.64-7.58 (2H, m), 7.46-7.40 (1H, m), 7.26-7.21 (1H, m), 7.08(1H, t, J=7.5 Hz), 6.95 (1H, d, J=8.4 Hz), 6.64 (1H, t, J=75 Hz),5.92-5.86 (1H, m), 5.24-5.13 (2H, m), 4.64 (2H, d, J=5.1 Hz), 4.22-4.14(4H, m), 2.65-2.58 (2H, m), 1.49 (3H, t, J=6.9 Hz)

Example 355

Using the compound obtained in Example 347 and 3-bromopentane, whitepowderyN-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamidewas obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz), 7.67(1H, s), 7.63-7.58 (2H, m), 7.46-7.40 (1H, m), 7.23 (1H, d, J=8.4 Hz),7.07 (1H, t, J=8.1 Hz), 6.95 (1H, d, J=8.1 Hz), 6.63 (1H, t, J=75 Hz),4.64 (2H, d, J=5.1 Hz), 4.33 (1H, qt, J=6.0, 5.1 Hz), 4.19 (2H, q, J=6.9Hz), 1.79-1.70 (4H, m), 1.49 (3H, t, J=6.9 Hz), 0.99 (6H, t, J=7.5 Hz)

Reference Example 94

Using the compound obtained in Reference Example 59 andchlorodifluoromethane, white powdery ethyl4-benzyloxy-3-difluoromethoxybenzoate was obtained following theprocedure of Example 4.

¹H-NMR (CDCl₃) δ: 7.90-7.80 (2H, m), 7.45-7.30 (5H, m), 7.03 (1H, d,J=8.4 Hz), 6.59 (1H, t, J=74.4 Hz), 5.23 (2H, s), 4.35 (2H, q, J=7.2Hz), 1.38 (3H, t, J=7.2 Hz)

Reference Example 95

Using the compound obtained in Reference Example 94, white powdery2-(4-benzyloxy-3-difluoromethoxyphenyl)-4-chloromethyloxazole wasobtained following the procedures of Reference Examples 3 to 5.

¹H-NMR (CDCl₃) δ: 7.90-7.80 (2H, m), 7.65 (1H, s), 7.45-7.30 (5H, m),7.06 (1H, d, J=7.2 Hz), 6.60 (1H, t, J=74.7 Hz), 5.20 (2H, s), 4.56 (2H,s)

Example 356

Using the compound obtained in Reference Example 95, white powdery3-{2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedures of Reference Examples 92 and 93and Examples 326 and 327.

¹H-NMR (CDCl₃) δ: 8.49 (1H, d, J=4.5 Hz), 7.76-7.72 (2H, m), 7.59 (1H,d, J=8.4 Hz), 7.57 (1H, s), 7.37-7.30 (1H, m), 7.02 (1H, d, J=8.4 Hz),6.59 (1H, t, J=75 Hz), 3.59 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz),2.57 (3H, s)

Example 357

Using the compound obtained in Example 356 and 2-bromopropane, whitepowdery 3-[2-(3-difluoromethoxy-4-isopropoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtainedfollowing the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.83-7.78 (2H, m), 7.58 (1H,d, J=8.4 Hz), 7.47 (1H, s), 7.34-7.30 (1H, m), 7.01 (1H, d, J=8.4 Hz),6.58 (1H, t, J=75 Hz), 4.67-4.57 (1H, m), 3.59 (2H, t, J=7.5 Hz), 3.01(2H, t, J=7.5 Hz), 2.57 (3H, s), 1.39 (6H, d, J=6.0 Hz)

Example 358

Using the compound obtained in Example 356 and allyl bromide, whitepowdery 3-[2-(4-allyloxy-3-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtainedfollowing the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.8, 1.2 Hz), 7.84-7.80 (2H, m),7.60-7.56 (1H, m), 7.47 (1H, d, J=1.2 Hz), 7.34-7.30 (1H, m), 7.01 (1H,d, J=8.4 Hz), 6.60 (1H, t, J=74.7 Hz), 6.10-6.00 (1H, m), 5.44 (1H, dd,J=17.4, 1.5 Hz), 5.33 (1H, dd, J=10.5, 1.5 Hz), 4.65 (2H, dt, J=5.1, 1.5Hz), 3.60 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 2.58 (3H, s)

Example 359

Using the compound obtained in Example 356 and 4-bromo-1-butene, whitepowdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtainedfollowing the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.8, 1.2 Hz), 7.84-7.78 (2H, m), 7.58(1H, d, J=7.5 Hz), 7.46 (1H, s), 7.34-7.30 (1H, m), 7.00 (1H, d, J=8.4Hz), 6.59 (1H, t, J=75 Hz), 5.94-5.85 (1H, m), 5.23-5.12 (2H, m), 4.12(2H, t, J=6.6 Hz), 3.60 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz),2.63-2.56 (5H, m)

Example 360

Using the compound obtained in Example 356 and(bromomethyl)cyclopropane, white powdery 3-[2-(4-cyclopropylmethoxy-3-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.8, 1.2 Hz), 7.83-7.79 (2H, m), 7.57(1H, d, J=7.5 Hz), 7.46 (1H, s), 7.34-7.30 (1H, m), 6.98 (1H, d, J=8.1Hz), 6.65 (1H, t, J=75 Hz), 3.92 (2H, d, J=7.2 Hz), 3.59 (2H, t, J=7.2Hz), 3.00 (2H, t, J=7.2 Hz), 2.57 (3H, s), 1.33-1.27 (1H, m), 0.69-0.63(2H, m), 0.40-0.34 (2H, m)

Example 361

Using the compound obtained in Example 356 and 1-bromopropane, whitepowdery 3-[2-(3-difluoromethoxy-4-propoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtainedfollowing the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, dd, J=4.8, 1.2 Hz), 7.84-7.78 (2H, m), 7.58(1H, d, J=8.1 Hz), 7.47 (1H, s), 7.43-7.30 (1H, m), 7.00 (1H, d, J=8.4Hz), 6.59 (1H, t, J=75 Hz), 4.03 (2H, t, J=6.6 Hz), 3.59 (2H, t, J=7.5Hz), 3.01 (2H, t, J=7.5 Hz), 2.58 (3H, s), 1.87 (2H, qt, J=7.2 Hz), 1.06(3H, t, J=7.2 Hz)

Example 362

Using the compound obtained in Example 356 and ethyl iodide, whitepowdery3-[2-(3-difluoromethoxy-4-ethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.5 Hz), 7.84-7.78 (2H, m), 7.59 (1H,d, J=8.4 Hz), 7.47 (1H, s), 7.34-7.30 (1H, m), 6.99 (1H, d, J=8.4 Hz),6.60 (1H, t, J=75 Hz), 4.15 (2H, q, J=6.9 Hz), 3.59 (2H, t, J=7.2 Hz),3.01 (2H, t, J=7.2 Hz), 2.57 (3H, s), 1.47 (3H, t, J=6.9 Hz)

Example 363

The compound obtained in Reference Example 95 was used and treatedfollowing the procedure of Example 228, followed by treatment accordingto the procedure of Example 229, yielding white powdery3-[2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.

¹H-NMR (CDCl₃) δ: 7.80-7.75 (2H, m), 7.71 (1H, dd, J=7.8, 1.8 Hz),7.46-7.40 (2H, m), 7.22-6.69 (3H, m), 6.59 (1H, t, J=75 Hz), 5.91 (1H,br s), 4.14 (2H, q, J=7.2 Hz), 3.42 (2H, t, J=7.5 Hz), 2.99 (2H, t,J=7.5 Hz), 1.48 (3H, t, J=7.2 Hz)

Example 364

Using the compound obtained in Example 363 and 4-bromo-1-butene, whitepowdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtainedfollowing the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.84-7.79 (2H, m), 7.71 (1H, dd, J=7.8, 1.8 Hz),7.46-7.39 (2H, m), 7.01-6.92 (3H, m), 6.59 (1H, t, J=75 Hz), 5.91-5.85(1H, m), 5.23-5.12 (2H, m), 4.18-4.09 (4H, m), 3.42 (2H, t, J=6.9 Hz),2.99 (2H, t, J=6.9 Hz), 2.60 (2H, m), 1.48 (3H, t, J=6.9 Hz)

Example 365

Using the compound obtained in Example 363 and allyl bromide, whitepowdery 3-[2-(4-allyloxy-3-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtainedfollowing the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.83-7.79 (2H, m), 7.70 (1H, dd, J=7.8, 1.8 Hz),7.46-7.39 (2H, m), 7.02-6.92 (3H, m), 6.60 (1H, t, J=74.7 Hz), 6.06-6.00(1H, m), 5.47-5.30 (2H, m), 4.66-4.63 (2H, m), 4.14 (2H, q, J=6.9 Hz),3.42 (2H, t, J=6.9 Hz), 2.99 (2H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)

Example 366

Using the compound obtained in Example 363 and ethyl iodide, whitepowdery3-[2-(3-difluoromethoxy-4-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-onewas obtained following the procedure of Example 3.

¹H-NMR (CDCl₃) δ: 7.84-7.80 (2H, m), 7.71 (1H, dd, J=7.8, 1.8 Hz),7.45-7.39 (2H, m), 7.00-6.91 (3H, m), 6.60 (1H, t, J=75 Hz) 4.18-4.10(4H, m), 3.42 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 1.50-1.44 (6H,m)

Reference Example 96

The compound obtained in Reference Example 95 was used and treatedfollowing the procedure of Reference Example 45, followed by treatmentaccording to the procedure of Reference Example 46, yielding pale yellowoily [2-(4-benzyloxy-3-difluoromethoxyphenyl)oxazol-4-yl]methylamine wasobtained.

¹H-NMR (CDCl₃) δ: 7.89-7.82 (2H, m), 7.61 (1H, s), 7.56-7.31 (5H, m),7.07 (1H, d, J=8.1 Hz), 6.62 (1H, t, J=75 Hz), 5.19 (2H, s), 3.83 (2H,s)

Example 367

The compound obtained in Reference Example 96 was used and treatedfollowing the procedure of Example 96, followed by treatment accordingto the procedure of Example 97, yielding white powderyN-[2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.

¹H-NMR (CDCl₃) δ: 8.59 (1H, br s), 8.39 (1H, d, J=4.5 Hz), 7.79-7.76(2H, m), 7.63-7.58 (2H, m), 7.37-7.28 (1H, m), 7.07 (1H, d, J=8.1 Hz),6.61 (1H, t, J=75 Hz), 6.16 (1H, s), 4.58 (2H, d, J=5.4 Hz), 2.76 (3H,s)

Example 368

Using the compound obtained in Example 367 and allyl bromide, whitepowdery N-[2-(4-allyloxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained followingthe procedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.39 (1H, d, J=4.5 Hz), 7.87-7.83(2H, m), 7.65 (1H, s), 7.60-7.57 (1H, m), 7.33-7.29 (1H, m), 7.10 (1H,d, J=8.4 Hz), 6.61 (1H, t, J=75 Hz), 6.10-5.99 (1H, m), 5.55 (1H, dd,J=17.1, 1.5 Hz), 5.34 (1H, dd, J=10.5, 1.5 Hz), 4.65 (2H, d, J=5.4 Hz),4.58 (2H, d, J=5.4 Hz), 2.76 (3H, s)

Example 369

Using the compound obtained in Example 367 and (bromomethyl)cyclobutane,white powdery N-[2-(4-cyclobutylmethoxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methyl picolinamidewas obtained following the procedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, d, J=4.5 Hz), 7.87-7.82(2H, m), 7.64 (1H, s), 7.59 (1H, d, J=8.4 Hz), 7.33-7.29 (2H, m), 7.01(1H, d, J=8.4 Hz), 6.59 (1H, t, J=75 Hz), 4.59 (1H, d, J=5.4 Hz), 4.03(2H, d, J=6.9 Hz), 2.90-2.82 (1H, m), 2.76 (3H, s), 2.22-2.13 (2H, m),2.00-1.84 (4H, m)

Example 370

Using the compound obtained in Example 367 and isobutyl bromide, whitepowdery N-[2-(3-difluoromethoxy-4-isobutoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained followingthe procedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, d, J=4.5 Hz), 7.87-7.83(2H, m), 7.64 (1H, s), 7.60-7.57 (1H, m), 7.33-7.28 (1H, m), 7.00 (1H,d, J=8.4 Hz), 6.59 (1H, t, J=75 Hz), 4.59 (1H, d, J=5.4 Hz), 3.81 (2H,d, J=6.9 Hz), 2.76 (3H, s), 2.22-2.09 (1H, m), 1.06 (6H, d, J=6.6 Hz)

Example 371

Using the compound obtained in Example 367 and 4-bromo-1-butene, whitepowdery N-[2-(4-but-3-enyloxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained followingthe procedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.59 (1H, br s), 8.39 (1H, d, J=4.5 Hz), 7.88-7.83(2H, m), 7.65 (1H, s), 7.60-7.57 (1H, m), 7.33-7.29 (1H, m), 7.01 (1H,d, J=8.4 Hz), 6.61 (1H, t, J=75 Hz), 5.94-5.83 (1H, m), 5.24-5.12 (2H,m), 4.59 (1H, d, J=5.4 Hz), 4.13 (2H, t, J=6.6 Hz), 2.76 (3H, s),2.63-2.57 (2H, m)

Example 372

Using the compound obtained in Example 367 and(bromomethyl)cyclopropane, white powdery N-[2-(4-cyclopropylmethoxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methyl picolinamidewas obtained following the procedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, d, J=4.5 Hz), 7.86-7.83(2H, m), 7.65 (1H, s), 7.59 (1H, d, J=8.4 Hz), 7.33-7.28 (1H, m), 7.00(1H, d, J=8.4 Hz), 6.66 (1H, t, J=75 Hz), 4.59 (2H, d, J=5.4 Hz), 3.93(2H, d, J=6.9 Hz), 2.76 (3H, s), 1.33-1.24 (1H, m), 0.70-0.64 (2H, m),0.41-0.35 (2H, m)

Example 373

The compound obtained in Reference Example 96 was used and treatedfollowing the procedure of Example 96, followed by treatment accordingto the procedure of Example 97, yielding white powderyN-[2-(3-difluoromethoxy-4-hydroxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.

¹H-NMR (CDCl₃) δ: 8.59 (1H, br s), 8.24 (1H, dd, J=7.8, 1.2 Hz),7.81-7.78 (2H, m), 7.63 (1H, s), 7.46-7.40 (1H, m), 7.11-7.05 (2H, m),6.96 (1H, d, J=8.4 Hz), 6.62 (1H, t, J=75 Hz), 5.87 (1H, br s), 4.62(2H, d, J=5.4 Hz), 4.19 (2H, q, J=6.9 Hz), 1.50 (3H, t, J=6.9 Hz)

Example 374

Using the compound obtained in Example 373 and 2-bromopropane, whitepowdery N-[2-(3-difluoromethoxy-4-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following theprocedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.24 (1H, dd, J=7.8, 2.1 Hz),7.85-7.82 (2H, m), 7.64 (1H, s), 7.45-7.39 (1H, m), 7.09-7.01 (2H, m),6.95 (1H, d, J=8.1 Hz), 6.59 (1H, t, J=75 Hz), 4.71-4.61 (5H, m), 4.19(2H, q, J=6.9 Hz), 1.51 (3H, t, J=6.9 Hz), 1.40 (6H, d, J=6.9 Hz)

Example 375

Using the compound obtained in Example 373 and(bromomethyl)cyclopropane, white powdery N-[2-(4-cyclopropylmethoxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy benzamidewas obtained following the procedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.59 (1H, br s), 8.24 (1H, dd, J=7.8, 2.1 Hz),7.85-7.82 (2H, m), 7.64 (1H, s), 7.45-7.39 (1H, m), 7.09-6.94 (3H, m),6.66 (1H, t, J=75 Hz), 4.62 (2H, d, J=5.4 Hz), 4.19 (2H, q, J=6.9 Hz),3.93 (2H, d, J=8.4 Hz), 1.50 (3H, t, J=6.9 Hz), 1.34-1.24 (1H, m),0.71-0.64 (2H, m), 0.41-0.35 (2H, m)

Example 376

Using the compound obtained in Example 373 and 1-bromopropane, whitepowdery N-[2-(3-difluoromethoxy-4-propoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following theprocedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz),7.87-7.83 (2H, m), 7.64 (1H, s), 7.42 (1H, t, J=7.5 Hz), 7.09-6.85 (3H,m), 6.35 (1H, t, J=75 Hz), 4.62 (2H, d, J=6.0 Hz), 4.19 (2H, q, J=6.6Hz), 4.04 (2H, t, J=6.0 Hz), 1.91-1.84 (2H, m), 1.50 (3H, t, J=6.9 Hz),1.07 (3H, t, J=6.9 Hz)

Example 377

Using the compound obtained in Example 373 and allyl bromide, whitepowdery N-[2-(4-allyloxy-3-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following theprocedure of Example 98.

¹H-NMR (CDCl₃) δ: 8.60 (1H, br s), 8.23 (1H, dd, J=7.8, 1.8 Hz),7.86-7.83 (2H, m), 7.64 (1H, s), 7.42 (1H, t, J=7.5 Hz), 7.10-6.97 (3H,m), 6.61 (1H, t, J=75 Hz), 6.07-6.01 (1H, m), 5.49-5.32 (2H, m),4.68-4.61 (4H, m), 4.19 (2H, q, J=6.9 Hz), 1.50 (3H, t, J=6.9 Hz)

Reference Example 97

Using ethyl 3,4-dihydroxybenzoate and chlorodifluoro methane, whitepowdery ethyl 3,4-bis-difluoromethoxybenzoate was obtained following theprocedure of Example 4.

¹H-NMR (CDCl₃) δ: 8.00-7.90 (2H, m), 7.31 (1H, d, J=8.1 Hz), 6.60 (1H,t, J=72.9 Hz), 6.57 (1H, t, J=72.9 Hz), 4.39 (2H, q, J=7.2 Hz), 1.40(3H, t, J=7.2 Hz)

Reference Example 98

Using the compound obtained in Reference Example 97, white powdery2-(3,4-bis-difluoromethoxyphenyl)-4-chloromethyl oxazol was obtainedfollowing the procedures of Reference Examples 3 to 5.

¹H-NMR (CDCl₃) δ: 7.95-7.90 (2H, m), 7.73 (1H, s), 7.35 (1H, d, J=8.4Hz), 6.60 (1H, t, J=72.9 Hz), 6.59 (1H, t, J=72.9 Hz), 4.57 (2H, s)

Example 378

Using the compound obtained in Reference Example 98, white powdery3-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-onewas obtained following the procedure of Example 190.

¹H-NMR (CDCl₃) δ: 7.89-7.84 (2H, m), 7.71 (1H, dd, J=7.5, 1.8 Hz),7.48-7.41 (2H, m), 7.32 (1H, d, J=8.4 Hz), 7.01-6.93 (2H, m), 6.58 (1H,t, J=75 Hz), 6.57 (1H, t, J=75 Hz), 4.14 (2H, q, J=6.9 Hz), 3.43 (2H, t,J=6.9 Hz), 3.00 (2H, t, J=6.9 Hz), 1.48 (3H, t, J=6.9 Hz)

Reference Example 99

The compound obtained in Reference Example 98 was used and treatedfollowing the procedure of Reference Example 45, followed by treatmentaccording to the procedure of Reference Example 46, yielding pale yellowoily [2-(3,4-bis-difluoromethoxy phenyl)oxazol-4-yl]-methylamine.

¹H-NMR (CDCl₃) δ: 7.92-7.88 (2H, m), 7.58 (1H, s), 7.34 (1H, d, J=8.4Hz), 6.60 (1H, t, J=75 Hz), 6.59 (1H, t, J=75 Hz), 3.85 (2H, s)

Example 379

Using the compound obtained in Reference Example 99, white powderyN-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained following the procedure of Example 96.

¹H-NMR (CDCl₃) δ: 8.61 (1H, br s), 8.40 (1H, dd, J=7.5, 1.5 Hz),7.93-7.88 (2H, m), 7.70 (1H, s), 7.60 (1H, d, J=1.5 Hz), 7.58-7.31 (2H,m), 6.60 (1H, t, J=75 Hz), 6.58 (1H, t, J=75 Hz), 4.60 (2H, dd, J=6.0,1.2 Hz), 2.77 (3H, s)

Example 380

Using the compound obtained in Reference Example 99, white powderyN-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamidewas obtained following the procedure of in Example 1.

¹H-NMR (CDCl₃) δ: 8.59 (1H, br s), 8.23 (1H, dd, J=7.5, 1.8 Hz),7.94-7.88 (2H, m), 7.70 (1H, s), 7.46-7.33 (2H, m), 7.07 (1H, t, J=7.5Hz), 6.95 (1H, d, J=8.4 Hz), 6.60 (1H, t, J=75 Hz), 6.59 (1H, t, J=75Hz), 4.63 (2H, d, J=6.0 Hz), 4.19 (2H, q, J=6.9 Hz), 1.50 (3H, t, J=6.9Hz)

Example 381

Using the compound obtained in Reference Example 98, white powdery3-[2-(3,4-bis-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-onewas obtained following the procedure of Example 356.

¹H-NMR (CDCl₃) δ: 8.51 (1H, br s), 7.88-7.85 (2H, m), 7.59 (1H, d, J=8.4Hz), 7.53 (1H, s), 7.35-7.30 (2H, m), 6.58 (1H, t, J=75 Hz), 6.57 (1H,t, J=75 Hz), 3.60 (2H, t, J=6.3 Hz), 3.02 (2H, t, J=6.3 Hz), 2.58 (3H,s)

Example 382

Using the compound obtained in Example 347 and the compound obtained inReference Example 85, white powdery N-{2-[4-difluoromethoxy-3-(2,2-difluoroethoxy)phenyl]-oxazol-4-ylmethyl}-2-ethoxybenzamide was obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.55 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz),7.71-7.65 (3H, m), 7.46-7.41 (1H, m), 7.29 (1H, s), 7.08 (1H, t, J=8.1Hz), 6.96 (1H, d, J=8.1 Hz), 6.59 (1H, t, J=74.1 Hz), 6.15 (1H, tt,J=54.9, 4.2 Hz) 4.64 (2H, d, J=5.4 Hz), 4.32 (2H, td, J=12.9, 4.2 Hz),4.20 (2H, q, J=6.9 Hz) 1.50 (3H, t, J=6.9 Hz)

Example 383

Using the compound obtained in Example 347 and1,1,1-trifluoro-2-iodoethane, white powderyN-{2-[4-difluoromethoxy-3-(2,2,2-trifluoroethoxy)phenyl]-oxazol-4-ylmethyl}-2-ethoxybenzamide was obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz),7.75-7.68 (3H, m), 7.46-7.40 (1H, m), 7.30 (1H, d, J=8.4 Hz), 7.08 (1H,t, J=8.1 Hz), 6.96 (1H, d, J=8.1 Hz), 6.60 (1H, t, J=74.1 Hz), 4.63 (2H,d, J=5.4 Hz), 4.49 (2H, q, J=8.1 Hz), 4.20 (2H, q, J=6.9 Hz) 1.50 (3H,t, J=6.9 Hz)

Example 384

Using the compound obtained in Example 17 and 2-bromo propane, colorlessoilyN-[2-(4-methoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamidewas obtained following the procedure of Example 19.

¹H-NMR (CDCl₃) δ: 8.58 (1H, br s), 8.39 (1H, dd, J=4.8, 1.2 Hz),7.63-7.57 (4H, m), 7.33-7.28 (1H, m), 6.93 (1H, d, J=8.4 Hz), 4.68 (1H,sept., J=6.3 Hz), 4.59 (2H, d, J=5.7 Hz), 3.89 (3H, s), 2.76 (3H, s),1.41 (6H, d, J=6.3 Hz)

Example 385

Using the compound obtained in Example 347 and (bromomethyl)cyclobutane,white powderyN-[2-(3-Cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamidewas obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br s), 8.24 (1H, dd, J=7.8, 1.8 Hz),7.67-7.58 (3H, m), 7.50-7.40 (1H, m), 7.23 (1H, d, J=8.4 Hz), 7.08 (1H,t, J=8.1 Hz), 6.96 (1H, d, J=8.1 Hz), 6.63 (1H, t, J=75 Hz), 4.64 (2H,d, J=5.1 Hz), 4.19 (2H, q, J=6.9 Hz), 4.08 (2H, d, J=6.6 Hz) 2.86-2.82(1H, m), 2.19-2.12 (2H, m), 2.04-1.87 (4H, m), 1.50 (3H, t, J=6.9 Hz)

The chemical structures of the compounds obtained above in the ReferenceExamples and Examples are shown below in Tables 1 to 40.

TABLE 1

Ref. Ex. No. R^(a) R^(b) 5 Methyl Benzyl 11 Methyl

17 Methyl

23 Methyl —CH₂CF₃ 32 —CH₂CF₃

35 Ethyl Ethyl 38 Methyl Methyl 44 —CHF₂ Benzyl 55 Benzyl Benzyl 58Methyl Ethyl 63 Benzyl Ethyl 68 Methyl iso-Propyl

TABLE 2

Ex. No. R^(c) 1 Benzyl 2 H 3

4 —CH₂CF₃ 5 n-Butyl 6 Cyclopentyl 7

8

9 Ethyl 10

11 n-propyl 12 iso-propyl 13

14 iso-Butyl 15 —CH₂CH₂CF₃ 92 Methyl —OEt: Ethoxy

TABLE 3

Ex. No. Ar^(a) 25 2-Trifluoromethylphenyl 322-(2,2,2-Trifluoroethoxy)phenyl 37 2-iso-Propoxyphenyl 38 2-Methylphenyl39 2-Ethylphenyl 40 2-Chlorophenyl 41 5-Fluoro-2-methoxyphenyl 424-Fluoro-2-methoxyphenyl 43 6-Fluoro-2-methoxyphenyl 442-Methylthiophenyl 46 2-Methoxyphenyl 47 2-Trifluoromethoxyphenyl 482-n-Propoxyphenyl 51 2-n-Butoxyphenyl 52 2-iso-Butoxyphenyl 542-Ethylthiophenyl 56 2,6-Dimethoxyphenyl 60 2-Methanesulfonylphenyl

TABLE 4

Ex. No. Ar^(b) 63 2-Methoxyphenyl 64 2-Methylthiophenyl 664-Fluoro-2-methoxyphenyl 67 2-iso-Propoxyphenyl 686-Fluoro-2-methoxyphenyl 71 2-n-Propoxyphenyl 72 2-n-Butoxyphenyl 732-iso-Butoxyphenyl

TABLE 5

Ex. No. Ar^(c) 78 2-Methoxyphenyl 79 2-Methylphenyl 80 2-n-Propoxyphenyl81 2-iso-Propoxyphenyl 82 4-Chloro-2-methoxyphenyl

TABLE 6

Ex. No. Ar^(d) 85 2-n-Propoxyphenyl 86 2-Trifluoromethylphenyl 882-Ethoxyphenyl 89 4-Ethoxyphenyl 90 5-Methoxy-2-trifluoromethoxyphenyl91 3-Ethoxyphenyl OEt: Ethoxy

TABLE 7

Ex. No. Ar^(e) R^(d) R^(e) 23 2-Trifluoromethylphenyl Methyl Benzyl 242-Trifluoromethylphenyl Methyl H 26 2-Trifluoromethylphenyl Methyl

30 2-(2,2,2- Methyl Benzyl Trifluoroethoxy)phenyl 31 2-(2,2,2- Methyl HTrifluoroethoxy)phenyl 33 2-Methoxyphenyl Methyl Benzyl 342-Methoxyphenyl Methyl H 35 2-Methoxyphenyl Methyl cyclo-Pentyl 832-Ethoxyphenyl —CH₂CF₃

93 2-Ethoxyphenyl Methyl Methyl

TABLE 8

Ex. No. R^(f) R^(g) 16 Methyl Benzyl 17 Methyl H 18 Methyl Cyclopentyl19 Methyl —CH₂CF₃ 20 Methyl Ethyl 21 Methyl Allyl 22 Methyl

36 Methyl

62 Methyl iso-Butyl 84 —CH₂CF₃

94 Methyl Methyl 96 —CHF₂ Benzyl 97 —CHF₂ H 98 —CHF₂

384 Methyl iso-Propyl

TABLE 9

Ex. No. R^(h) R^(i) 27 Ethyl Benzyl 28 Ethyl H 29 Ethyl Cyclopentyl 45 H

50 Ethyl

53 iso-Propyl

57 Methyl

58 iso-Butyl

61 n-Propyl

65 Ethyl iso-Butyl 69 Methyl iso-Butyl 70 iso-Butyl iso-Butyl 74iso-Propyl iso-Butyl 76 Methyl —CH₂CF₃ 77 Ethyl —CH₂CF₃ 95 Methyl Methyl

TABLE 10

Ex. No. Ar^(f) R^(j) R^(k) 49

Methyl

55

Methyl

59

Methyl

75

Methyl iso-Butyl 87

Ethyl Ethyl 99

Methyl

Me: Methyl

TABLE 11

Ex. No. R^(l) R^(m) 101 Methyl H 102 Methyl

103 Methyl Ethyl 104 Methyl Allyl 105 Methyl Cyclopentyl 106 Methyliso-Butyl 107 Methyl n-Propyl 108 Methyl

109 Methyl n-Butyl 110 Methyl

111 Methyl iso-Propyl 112 Methyl —CH₂CF₃ 113 Methyl

114 Methyl

115 Methyl

116 Methyl

117 Methyl

118 Methyl

119 Methyl

120 Methyl

121 Methyl

122 Methyl

182 Ethyl Ethyl 190 Benzyl Ethyl 191 H Ethyl 192 iso-Propyl Ethyl 228—CHF₂ Benzyl 229 —CHF₂ H 230 —CHF₂ iso-Propyl —OEt: Ethoxy

TABLE 12

Ex. No R^(n) 169 iso-Propyl 170

171 Cyclopentyl 172 Ethyl 173 iso-Butyl 174 Allyl 175 —CH₂CF₃ —OMe:Methoxy

TABLE 13

Ex. No. R^(o) 194 H 195 Ethyl 196 Cyclopentyl 197 iso-Propyl 198

199

200 Allyl 201

203 —CH₂CF₃

TABLE 14

Ex. No. R^(p) 207 H 208

209 Ethyl 210 iso-Propyl 211 Allyl 212

213 —CH₂CF₃ 214

TABLE 15

Ex. No. R^(q) 164 Benzyl 166 Allyl 177

189 Ethyl 224 iso-Propyl

TABLE 16

Ex. No. R^(r) 220 H 221

225 Ethyl 226 Allyl 227 iso-Propyl

TABLE 17

Ex. No. Ar^(g) 178 2-Allyloxyphenyl 184 3-Ethoxyphenyl 1854-Ethoxyphenyl 205 2-n-Propoxyphenyl 216 2-iso-Propoxyphenyl 2182-Methylphenyl —OEt: Ethoxy

TABLE 18 Ex. No. Chemical Structure 165

168

176

179

223

231

232

233

234

235

TABLE 19

Ex. No. R^(s) 136 H 137

138 Ethyl 139 iso-Propyl 140 Allyl 141

142 iso-Butyl 143 n-Propyl 144 Cyclopentyl 145

146

147 n-Butyl 148

149

150 —CH₂CH₂Ph 151 —CH₂CH₂CH₂Ph 152

153

154

155 —CH₂CF₃ 156

157

158 Cyclohexyl 159

Ph: Phenyl

TABLE 20

Ex. No. R^(t) R^(u) 125 Methyl H 126 Methyl

127 Methyl iso-Butyl 128 Methyl Cyclopentyl 129 Methyl —CH₂CF₃ 131 EthylH 132 Ethyl Cyclopentyl 133 Ethyl

134 Ethyl iso-Butyl

TABLE 21 Ex. No. Chemical Structure 123

161

162

163

181

183

187

188

TABLE 22

Ex. No. Ar^(h) R^(v) R^(w) 193 2-n-Propoxyphenyl Methyl Benzyl 2022-n-Propoxyphenyl Methyl —CH₂CF₃ 204 2-n-Propoxyphenyl Ethyl Ethyl 2062-iso-Propoxyphenyl Methyl Benzyl 215 2-iso-Propoxyphenyl Ethyl Ethyl217 2-Methylphenyl Ethyl Ethyl 219 2-Methylphenyl Methyl Benzyl 2222-Benzyloxyphenyl Methyl iso-Propyl

TABLE 23

Ex. No. Ar^(i) R^(x) R^(y) 100 2-Ethoxyphenyl Methyl Benzyl 1243-Methoxypyridyl Methyl Benzyl 130 3-Ethoxypyridyl Methyl Benzyl 1353-Methylpyridyl Methyl Benzyl 160 2-Pyridyl Methyl Benzyl 1672-MethoxyPhenyl Methyl Benzyl 180 3-MethylPyridyl Ethyl Ethyl 1863-MethylPyridyl Benzyl Benzyl

TABLE 24 Ex. No. Chemical Structure 236

237

238

239

240

TABLE 25 Ex. No. Chemical Structure 241

242

243

244

245

TABLE 26 Ex. No. Chemical Structure 246

247

248

249

250

TABLE 27 Ex. No. Chemical Structure 251

252

253

254

255

256

TABLE 28 Ex. No. Chemical Structure 257

258

259

260

261

TABLE 29 Ex. No. Chemical Structure 262

263

264

265

TABLE 30 Ref. Ex. No. Chemical Structure 89

90

91

92

93

95

TABLE 31 Ref. Ex. No. Chemical Structure 96

98

99

TABLE 32

Ex. No. R_(A) R_(B) 325 Methyl 1-Ethylpropyl 346 Difluoromethyl Benzyl347 Difluoromethyl H 348 Difluoromethyl iso-Butyl 349 DifluoromethylEthyl 350 Difluoromethyl n-Propyl 351 Difluoromethyl Allyl 352Difluoromethyl iso-Propyl 353 Difluoromethyl Cyclopropylmethyl 354Difluoromethyl 3-Butenyl 355 Difluoromethyl 1-Ethylpropyl 373 HDifluoromethyl 374 iso-Propyl Difluoromethyl 375 CyclopropylmethylDifluoromethyl 376 n-Propyl Difluorornethyl 377 Allyl Difluoromethyl 380Difluoromethyl Difluoromethyl 382 Difluoromethyl 2,2-Difluoroethyl 383Difluoromethyl 2,2,2-Trifluoroethyl 385 Difluoromethyl Cyclobutylmethyl OEt: Ethoxy

TABLE 33

Ex. No. R_(C) R_(D) 324 Methyl 1-Ethylpropyl 338 Difluoromethyl Ethyl339 Difluoromethyl Allyl 340 Difluoromethyl n-Propyl 341 Difluoromethyliso-Propyl 342 Difluoromethyl 1-Ethylpropyl 343 Difluoromethyl 3-Butenyl344 Difluoromethyl iso-Butyl 345 Difluoromethyl Cyclobutylmethyl 367 HDifluoromethyl 368 Allyl Difluoromethyl 369 CyclobutylmethylDifluoromethyl 370 iso-Butyl Difluoromethyl 371 3-Butenyl Difluoromethyl379 Difluoromethyl Difluoromethyl

TABLE 34

Ex. No. R_(E) R_(F) 313 Methyl Difluoromethyl 314 Methyl2,2-Difluoroethyl 315 Methyl 2-Fluoro ethyl 334 Difluoromethyl Ethyl 335Difluoromethyl Allyl 336 Difluoromethyl Cyclopropylmethyl 337Difluoromethyl 3-Butenyl 363 H Difluoromethyl 364 3-ButenylDifluoromethyl 365 Allyl Difluoromethyl 366 Ethyl Difluoromethyl 378Difluoromethyl Difluoromethyl  OEt: Ethoxy

TABLE 35

Ex. No. R_(G) R_(H) 308 Methyl Difluoromethyl 309 Methyl2,2-Difluoroethyl 310 Methyl 2-Fluoroethyl 311 Methyl sec-Butyl 312Methyl 1-Ethylpropyl 317 H 2,2-Difluoroethyl 318 Ethyl 2,2-Difluoroethyl319 iso-Propyl 2,2-Difluoroethyl 327 Difluoromethyl H 328 DifluoromethylCyclopropylmethyl 329 Difluoromethyl n-Propyl 330 Difluoromethyl Allyl331 Difluoromethyl 3-Butenyl 332 Difluoromethyl iso-Propyl 333Difluoromethyl Ethyl 356 H Difluoromethyl 357 iso-Propyl Difluoromethyl358 Allyl Difluoromethyl 359 3-Butenyl Difluoromethyl 360Cyclopropylmethyl Difluoromethyl 361 n-Propyl Difluoromethyl 362 EthylDifluoromethyl 381 Difluoromethyl Difluoromethyl

TABLE 36

Ex. No. R_(I) R_(J) R_(K) 267 Methyl Benzyl Difluoromethyl 268 MethylBenzyl 2-Fluoroethyl 269 Methyl Benzyl 2,2-Difluoroethyl 270 Methyl HDifluoromethyl 271 Methyl H 2-Fluoroethyl 272 Methyl H 2,2-Difluoroethyl273 Methyl iso-Propyl Difluoromethyl 274 Methyl Ethyl Difluoromethyl 275Methyl iso-Propyl 2-Fluoroethyl 276 Methyl 3-Butenyl 2-Fluoroethyl 277Methyl iso-Butyl 2-Fluoroethyl 278 Methyl iso-Propyl 2,2-Difluoroethyl279 Methyl n-Propyl 2,2-Difluoroethyl 280 Methyl Ethyl 2,2-Difluoroethyl281 Methyl Allyl 2,2-Difluoroethyl 282 Methyl 3-Butenyl2,2-Difluoroethyl 283 Methyl Cyclopropylmethyl 2,2-Difluoroethyl 284Methyl 2,2-Difluoroethyl 2,2-Difluoroethyl 285 Methyl iso-Butyl2,2-Difluoroethyl 288 Ethyl Ethyl Difluoromethyl 289 Ethyl Ethyl2-Fluoroethyl 290 Ethyl Ethyl 2,2-Difluoroethyl 292 Ethyl EthylTrifluoromethyl 293 Methyl Cyclopropylmethyl Trifluoromethyl

TABLE 37 Ex. No. Chemical Structure 266

286

287

291

294

295

TABLE 38 Ex. No. Chemical Structure 296

297

298

299

300

301

302

303

TABLE 39 Ex. No. Chemical Structure 304

305

306

307

316

320

321

TABLE 40 Ex. No. Chemical Structure 322

323

326

Test Example 1 Phosphodiesterase (PDE)4 Inhibitory Activity EvaluationTest

(1) Large Scale Plasmid Preparation

Plasmid containing genes (HPDE4D) coding for human PDE4D3 cDNA (storedin Otsuka America Pharmaceutical, Inc., Maryland Research Laboratories)was transformed in E. coli, cultured on a large scale, and purifiedusing an EndoFree™ Plasmid Maxi Kit (Qiagen).

(2) Abundant Expression and Purification of PDE4D

COS-7 cells derived from African green monkey kidneys were passagecultured in D-MEM media containing 100 units/ml penicillin, 100 μg/mlstreptomycin, and 10% FBS. The cells were transfected with the plasmidprepared in (1) above using Lipofectamine™ 2000 (hereinafter referred toas “LF2000”, Invitrogen), following the manufacturer's protocol. TheCOS-7 cells were inoculated in a 10 cm culture dish on the previous dayso as to be 90% confluent on the day of transfection. Culture disheseach containing a plasmid solution (solution A) in which 24 μg ofplasmid was diluted in 1.5 ml Opti-MEM I Reduced Serum Medium(Invitrogen) and an LF2000 solution (solution B) in which 60 μl ofLF2000 was diluted in 1.5 ml Opti-MEM I Reduced Serum Medium wereseparately allowed to stand for 5 minutes at room temperature. SolutionsA and B were then mixed and the mixture was allowed to stand for 20minutes at room temperature. The mixture was added to the culturedcells, and incubated at 37° C. (5% CO₂) overnight. On the following day,the medium was replaced, and the mixture was further incubated overnightto harvest the cells in the following manner. The cells were washed withPBS (Sigma) once, and 10 ml of a Trypsin-EDTA solution (Sigma) was addedto each culture dish. After the solution was distributed to each of theculture dishes, the cells were detached, and the dishes were allowed tostand for about 5 minutes at 37° C. The detached cells from the disheswere suspended in media, collected into centrifuge tubes, andcentrifuged at 1200 rpm for 5 minutes at 4° C., and supernatants wereremoved. The cells were further washed with PBS, and stored at −80° C.KHEM buffer (100 mM Hepes, 50 mM KCl, 10 mM EGTA, 1.92 mM MgCl₂, pH 7.4)containing 1 mM DTT, 1 μg/ml antipain, 1 μg/ml aprotinin, 1 μg/mlleupeptin, 1 μg/ml pepstatin A, 157 μg/ml benzamidine, and 120 μg/mlPefabloc SC was added to the stored cells, and the contents were movedto a glass homogenizer to be homogenized on ice. The cell suspension wascentrifuged at 1000 rpm for 5 minutes at 4° C., and the supernatant wasfurther centrifuged at 14000 rpm for one hour. After centrifugation, thesupernatant was dispensed into new tubes as PDE4D enzyme solutions, andstored in a deep freezer.

(3) Determination on Dilution Ratio of PDE4D Enzyme Solutions

The PDE4D enzyme solutions prepared in (2) above were dissolved in 20 mMTris-HCl solution (pH 7.4) to give 10-, 25-, 50-, 100-, 200-, 400-, and800-fold dilutions of the enzyme solutions. PDE4D activities weremeasured according to (4) below. The percentage of catalyzed cAMP tototal cAMP was calculated, and such a dilution, in which the percentagewas between 10% and 30%, was adopted in the inhibitory study below.

(4) Measurement of PDE4D Inhibitory Activity

Necessary amounts of test compounds were weighed, and 100%dimethylsulfoxide (DMSO) was added thereto to adjust the concentrationto 10 mM. The solutions were stored in a freezer as stock solutions ofeach test compound. After being thawed when required, the solutions werediluted 20-fold with 100% DMSO to give a 500 μM concentration. Further,10-fold serial dilutions were made with 100% DMSO to prepare testcompounds of different concentrations. 2 μl of solutions containing oneof each of the test compound were separately added into 1.2 ml tubes inwhich 23 μl of 20 mM Tris-HCl (pH 7.4) had been placed beforehand. 25 μlof a PDE4D enzyme solution diluted at an optimal ratio determined in (3)above were added on ice to each of the tubes, and 50 μl of a substratesolution containing 2 μM[³H] cAMP prepared by dilution with a 20 mMTris-HCl (pH 7.4) containing 10 mM MgCl₂ was added thereto. The finalDMSO concentration in the reaction liquid was 2%. After mixing, themixture was incubated for 10 minutes at 30° C. At the completion of theincubation, the tubes were placed in a bath containing boiling water for3 minutes, and the reaction was stopped. After cooling the tubes in ice,25 μl solution of 0.2 mg/ml snake venom was added thereto, and aftermixing the mixture was incubated for 10 minutes at 30° C. At thecompletion of the incubation, 0.4 ml of a Dowex 1×8 resin solutionprepared in an EtOH:H₂O (1:1) solution was added thereto. After mixing,the tubes were allowed to stand at room temperature for at least anhour. 50 μl of the supernatant in one of each of the tubes was moved toone of the wells of a topcount plate, and the plate was dried overnight.³H radioactivity (cpm) was measured using a TopCount™.

The IC₅₀ values (concentration which produced 50% inhibition ofsubstrate hydrolysis) for the test compounds were determined with theExcel (Microsoft Excel 2000 SR-1) statistical package using regressionanalysis function.

The results are shown in Table 41. The table demonstrates that compoundsrepresented by formula (1) have the outstanding PDE4 inhibitoryactivities.

In the structural formulae shown in the following table, -Me is a methylgroup, -Et is an ethyl group, —OMe is a methoxy group, —OEt is an ethoxygroup, and —SMe is a methylthio group.

TABLE 41 PDE 4 Ex. No. Chemical Structure (IC₅₀: nM) 3

<50 14

<50 18

<50 19

<50 21

<50 22

<50 29

<50 32

<50 35

<50 36

<50 42

<50 43

<50 44

<50 61

<50 62

<50 63

<50 76

<50 98

<50 99

<50 102

<50 103

<50 104

<50 108

<50 111

<50 112

<50 116

<50 126

<50 129

<50 132

<50 133

<50 137

<50 138

<50 139

<50 140

<50 141

<50 143

<50 146

<50 153

<50 155

<50 157

<50 159

<50 166

<50 169

<50 170

<50 172

<50 174

<50 177

<50 181

<50 182

<50 195

<50 208

<50 224

<50 232

<50 274

<50 275

<50 276

<50 278

<50 280

<50 281

<50 283

<50 284

<50 285

<50 289

<50 290

<50 299

<50 304

<50 305

<50 309

<50 311

<50 312

<50 314

<50 315

<50 318

<50 324

<50 328

<50 329

<50 330

<50 331

<50 332

<50 333

<50 334

<50 335

<50 336

<50 337

<50 338

<50 339

<50 340

<50 341

<50 342

<50 343

<50 344

<50 345

<50 348

<50 349

<50 350

<50 351

<50 352

<50 353

<50 354

<50 355

<50 382

<50 383

<50 384

<50

Test Example 2 Inhibitory Activity Measurement on TNF-α Production

TNF-α production inhibitory activity was evaluated according to thefollowing tests.

(1) Isolation of Mononuclear Cells from Mouse Peripheral Blood

Mononuclear cells were isolated from heparinized blood obtained frommale BALB/c mice (Charles River Laboratories, Japan) by density gradientcentrifugation using Lympholyte-M (Cedarlane Laboratories). Viable cellnumbers in the peripheral blood mononuclear cells were counted usingtrypan blue dye, and prepared in cell culture medium (RPMI 1640 mediumcontaining 10% FCS) to 1.25×10⁶ cells/ml.

(2) Induction of TNF-α Production

Test compounds were dissolved in DMSO, and test compound solutions werediluted for use in cell culture media. 20 μl test compound solutions ofdifferent concentrations and 160 μl peripheral blood mononuclear cellsuspensions were placed in a 96-well plate, and cultured for 30 minutes.20 μl (final concentration 1 μg/ml) lipopolysaccharide (LPS) derivedfrom E. coli (serotype 055:B5) was added thereto to induce THF-αproduction. The mixtures were then cultured at 37° C. for 5 hours, andthe culture supernatant was removed from each well.

(3) Measurement of TNF-α Concentration

TNF-α concentrations in the culture supernatants were measured by ELISA(OptEIA™ Set Mouse TNF-α, BD Pharmingen). The IC₅₀ values (concentrationwhich produced 50% inhibition of TNF-α production) for the testcompounds were determined with the Excel (Microsoft Excel 2000 SR-1)statistical package using regression analysis function.

The results obtained are shown in table 42.

TABLE 42 Test compounds TNF-α (IC₅₀: nM) Compound of Ex. 18 <50 Compoundof Ex. 43 <50 Compound of Ex. 126 <50 Compound of Ex. 157 <50 Compoundof Ex. 177 <50

The invention claimed is:
 1. An oxazole compound represented by Formula (1)

wherein R¹ is an aryl group which may have one or more substituents selected from the following (1-1) to (1-11): (1-1) hydroxy groups, (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups, (1-5) cyclo C₃₋₈ alkyl lower alkoxy groups, (1-6) cyclo C₃₋₈ alkyloxy groups, (1-7) cyclo C₃₋₈ alkenyloxy groups, (1-8) dihydroindenyloxy groups, (1-9) hydroxy lower alkoxy groups, (1-10) oxiranyl lower alkoxy groups, and (1-11) protected hydroxy groups; R² is an aryl group or a nitrogen atom-containing heterocyclic group each of which may have one or more substituents selected from the following (2-1) to (2-10): (2-1) hydroxy groups, (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted lower alkyl groups, (2-4) lower alkenyloxy groups, (2-5) halogen atoms, (2-6) lower alkanoyl groups other than a formyl group, (2-7) lower alkylthio groups, (2-8) lower alkylsulfonyl groups, (2-9) oxo groups, and (2-10) lower alkoxy lower alkoxy groups; and the nitrogen atom-containing heterocyclic group in R² is selected from imidazolidinyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindolyl, azocanyl, pyrrolyl, dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl and N-oxides thereof, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, carbazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxazolidinyl, isooxazolidinyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolyzinyl, benzothiazolyl, and benzothiadiazolyl; and W is a divalent group represented by Formula (i) or (ii): —Y¹-A¹-   Formula (i) —Y²—C(═O)—  Formula (ii) wherein A¹ is a lower alkenylene group, or a lower alkylene group which may have one or more substituents selected from the group consisting of hydroxy groups and lower alkoxycarbonyl groups, Y¹ is —C(═O)—, —C(═O)—N(R³)—, —S(O)_(m)—NH—, or —S(O)_(n)— wherein R³ is a hydrogen atom or a lower alkyl group, and m and n are each independently an integer from 0 to 2, and Y² is a piperazinediyl group, or a divalent group represented by Formula (iii): —C(═O)-A²-N(R⁵)—  Formula (iii) wherein A² is a lower alkylene group, and R⁵ is a hydrogen atom or a lower alkyl group; or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein R¹ is a phenyl group which has 1 to 3 substituents selected from the following (1-2), (1-3), (1-4) and (1-5): (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups, and (1-5) cyclo C₃₋₈ alkyl lower alkoxy groups; R² is a phenyl group or a pyridyl group each of which may have 1 to 3 substituents selected from the group consisting of the following (2-2), (2-3), (2-4) and (2-5): (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted lower alkyl groups, (2-4) lower alkenyloxy groups, and (2-5) halogen atoms; W is a divalent group represented by Formula (i): —Y¹-A¹-   Formula (i) wherein A¹ is a lower alkylene group, and Y¹ is —C(═O)— or —C(═O)—N(R³)— wherein R³ is a hydrogen atom.
 3. The compound according to claim 2, wherein R¹ is a phenyl group having two substituents selected from the following (1-2), (1-3), (1-4) and (1-5): (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups, and (1-5) cyclo C₃₋₈ alkyl lower alkoxy groups; R² is a phenyl group or a pyridyl group each of which may have 1 to 2 substituents selected from the following (2-2), (2-3), (2-4) and (2-5): (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted lower alkyl groups, (2-4) lower alkenyloxy groups, and (2-5) halogen atoms; and W is a divalent group represented by Formula (i): —Y¹-A¹-   Formula (i) wherein A¹ is a lower alkylene group, and Y¹ is —C(O)— —C(═O)— or —C(═O)—N(R³)— wherein R³ is a hydrogen atom.
 4. The compound according to claim 3, wherein R¹ is a phenyl group substituted on the phenyl ring with two lower alkoxy groups, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one cyclo C₃₋₈, C₃₋₈ alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl group with one lower alkoxy group and one lower alkenyloxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C₃₋₈ alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group, or a phenyl group substituted on the phenyl ring with two halogen-substituted lower alkoxy groups; R² is a lower alkoxyphenyl group, a lower alkenyloxyphenyl group, a halogen-substituted lower alkoxyphenyl group, a lower alkylpyridyl group, or a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen atom; and W is a divalent group represented by Formula (i): —Y¹-A¹-   Formula (i) wherein A¹ is a C₁₋₄ alkylene group, and Y¹ is —C(═O)— or —C(═O)—N(R³)— wherein R³ is a hydrogen atom.
 5. The compound according to claim 4, wherein R¹ is a phenyl group substituted on the phenyl ring with two lower alkoxy groups, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one cyclo C₃₋₈ alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl group with one lower alkoxy group and one lower alkenyloxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C₃₋₈ alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group, or a phenyl group substituted on the phenyl ring with two halogen-substituted lower alkoxy groups; R² is a lower alkoxyphenyl group, a lower alkenyloxy phenyl group, a halogen-substituted lower alkoxyphenyl group, a lower alkylpyridyl group, or a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen atom; and W is a divalent group represented by Formula (i): —Y¹-A¹-   Formula (i) wherein A¹ is a C₁₋₄ alkylene group, and Y¹ is —C(═O)—.
 6. The compound according to claim 4, wherein R¹ is a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C₃₋₈ alkyl lower alkoxy group, or a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group; R² is a lower alkoxyphenyl group or a lower alkylpyridyl group; and W is a divalent group represented by Formula (i): —Y¹-A¹-   Formula (i) wherein A¹ is a C₁₋₄ alkylene group, and Y¹ is —C(═O)—N(R³)— wherein R³ is a hydrogen atom.
 7. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt according to any one of claims 1 to 6 as an active ingredient and a pharmaceutically acceptable carrier.
 8. A method for treating dermatosis, the method comprising administering the compound or a pharmaceutically acceptable salt according to any one of claims 1 to 6 to a human or an animal in need thereof.
 9. A process for producing an oxazole compound represented by Formula (1):

wherein R¹, R² and W are the same as defined in claim 1, or a salt thereof, the process comprising a reaction of a compound represented by Formula (2):

wherein R² and W are the same as defined above, and X is a halogen atom, or a pharmaceutically acceptable salt thereof, with a compound represented by Formula (3):

wherein R¹ is the same as defined above, or a salt thereof.
 10. The compound or a pharmaceutically acceptable salt thereof according to claim 6, which is selected from the group consisting of the following compounds: N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-yl ethyl p-methylpicolinamide, N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide, N-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide, N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, N-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, N-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]2-ethoxybenzamide, N-[2-(3-cyclopropylmethoxy-4-d fluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, and N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamine, N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, and N-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
 11. A compound which is N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, having the structure:


12. A pharmaceutical composition comprising the compound according to claim 11 as an active ingredient and a pharmaceutically acceptable carrier.
 13. A method for treating dermatosis, the method comprising administering the compound according to claim 11 to a human or an animal in need thereof.
 14. A pharmaceutically acceptable salt of a compound, the compound being N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide and having the structure:


15. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to claim 14 as an active ingredient and a pharmaceutically acceptable carrier.
 16. A method for treating dermatosis, the method comprising: administering the pharmaceutically acceptable salt according to claim 14 to a human or an animal in need thereof. 